Methods

ABSTRACT

The disclosure provides the use of particular substituted heterocycle fused gamma-carboline compounds as pharmaceuticals for the treatment of residual symptoms of psychosis or schizophrenia. The disclosure also provides novel long acting injectable formulations of particular substituted heterocycle fused gamma-carboline compounds and use of such long acting injectable formulations for the treatment of residual symptoms of psychosis or schizophrenia.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 15/101,874, filed on Jun. 3, 2016, which is a U.S. National Stageapplication of PCT/US2014/068443, filed on Dec. 3, 2014, which claimspriority from U.S. Provisional Application Nos. 61/911,416 filed on Dec.3, 2013; 61/925,607 filed on Jan. 9, 2014; 61/975,702 filed on Apr. 4,2014; and 62/032,326 filed on Aug. 1, 2014, the contents of each ofwhich are incorporated by reference in their entirety.

TECHNICAL FIELD

The present invention relates to use of particular substitutedheterocycle fused gamma-carbolines as described herein, in free orpharmaceutically acceptable salt forms, as pharmaceuticals andpharmaceutical compositions as primary or adjunct therapy in thetreatment of acute and residual phases of schizophrenia, particularlyincluding the treatment of residual symptoms such as active socialavoidance, passive social withdrawal, emotional withdrawal, anxiety,tension, stereotyped thinking, and somatic concerns. The compoundsdisclosed herein can be used to treat both acute symptoms and residualsymptoms that appear during acute exacerbations but define the residualphase of the illness, e.g., schizophrenia, once the acute symptoms wane.Therefore, the compounds disclosed herein can be used alone or incombination with other antipsychotic medications as well as other activeagents that treat co-morbid disorders such depression and/or sleepdisorders. As the response profile across symptoms associated withschizophrenia may be particularly beneficial in improving socialfunction, the compounds disclosed herein can be used to improve socialintegration and social function. Such a response profile can bebeneficial to prodromal, exacerbation and residual phases ofschizophrenia.

BACKGROUND OF THE INVENTION

Psychosis, particularly schizophrenia affects 1.1% of the populationworldwide. This illness comprises three phases: prodromal phase, activephase and residual phase. Prodromal phase is an early phase whereinsubclinical signs and symptoms are observed. These symptoms may includeloss of interest in usual pursuits, withdrawal from friends and familymembers, confusion, trouble with concentration, feeling of listless andapathy. Active phase is characterized by exacerbations of positivesymptoms such as delusions, hallucinations and suspiciousness. Residualphase is characterized by negative symptoms such as emotionalwithdrawal, passive social withdrawal, and stereotyped thinking, andsymptoms of general psychopathology including active social avoidance,anxiety, tension, and somatic concerns. Residual phase symptoms areoften accompanied by depression, cognitive dysfunction and insomnia.Collectively, these residual phase symptoms are not well-treated by manyantipsychotic drugs currently available on the market and therefore areusually observed after the active phase symptoms have subsided aftertreatment. This phase of the illness is when patients would like toreturn to more productive and fulfilling lives, but since the residualnegative symptoms and cognitive impairment are not properly treated,this goal is frustrated. There remains an urgent need for anti-psychoticagents, which can treat not just the active or acute phase symptoms, butalso the residual phase symptoms of psychosis, e.g., schizophrenia.

Substituted heterocycle fused gamma-carbolines are known to be agonistsor antagonists of 5-HT₂ receptors, particularly 5-HT_(2A) and 5-HT_(2C)receptors, in treating central nervous system disorders. These compoundshave been disclosed in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017;6,713,471; U.S. RE39680, U.S. RE39679, U.S. Pat. Nos. 7,183,282 and7,071,186, as novel compounds and medical use for the treatment ofdisorders associated with 5-HT_(2A) receptor modulation such as obesity,anxiety, depression, psychosis, schizophrenia, sleep disorders, sexualdisorders, migraine, autism, conditions associated with cephalic pain,social phobias, and gastrointestinal disorders such as dysfunction ofgastrointestinal tract motility. PCT/US08/03340 and U.S. applicationSer. No. 10/786,935 also disclose methods of making substitutedheterocycle fused gamma-carbolines and uses of these gamma-carbolines asserotonin agonists and antagonists useful for the control and preventionof central nervous system disorders such as addictive behavior and sleepdisorders.

In addition, WO 2009/145900, WO 2011/133224, WO 2013/155505, WO2013/155504 and WO 2013/155506 teach further substituted heterocyclicfused gamma-carboline compounds and/or their use for the treatment ofone or more disorders involving the 5-HT_(2A), serotonin transporter(SERT) and/or dopamine D1/D2 pathways.

Although the above-cited references pertaining to substitutedheterocyclic fused gamma-carboline compounds teach treatment of certaindisorders associated with psychosis and/or depression, none of thesereferences disclose treatment of residual symptoms of psychosis,particularly residual symptoms of schizophrenia.

SUMMARY OF THE INVENTION

It has been discovered that particular substituted heterocycle fusedgamma-carboline compounds (the compounds described herein below) possessmechanisms of action that are believed to have the potential to yield afirst-in-class antipsychotic therapy. The Compounds of Formula I combinepotent serotonin 5-HT_(2A) receptor antagonism, dopamine receptorphosphoprotein modulation, or DPPM, glutamatergic modulation andserotonin reuptake inhibition into a single drug candidate for thetreatment of acute and residual schizophrenia. At dopamine D2 receptors,the Compounds of Formula I have dual properties and act as bothpost-synaptic antagonists and pre-synaptic partial agonists. TheCompounds of Formula I also stimulate phosphorylation of glutamatergicNMDA NR2B, or GluN2B, receptors in a mesolimbic specific manner. It isbelieved that this regional selectivity in the brain areas thought tomediate the efficacy of antipsychotic drugs, together with serotonergic,glutamatergic, and dopaminergic interactions, may result inantipsychotic efficacy for positive, negative, affective and cognitivesymptoms associated with schizophrenia. The serotonin reuptakeinhibition could allow for antidepressant activity for the treatment ofschizoaffective disorder, co-morbid depression, and/or as a stand-alonetreatment for major depressive disorder. It is believed that theCompounds of Formula I may also be useful for the treatment of bipolardisorder and other psychiatric and neurodegenerative disorders,particularly behavioral disturbances associated with dementia, autismand other CNS diseases. These features of the Compounds of Formula I maybe able to improve the quality of life of patients with schizophreniaand enhance social function to allow them to more fully integrate intotheir families and their workplace. In addition, the Compounds ofFormula I may be shown to treat disorders at either low-doses (e.g.,sleep, aggression and agitation) or high-doses (e.g., acute exacerbatedand residual schizophrenia, bipolar disorders, and mood disorders).

As the compounds described below are effective in treating not justacute symptoms, but also residual symptoms of psychosis, the inventiontherefore provides, in one aspect, methods of using the particularsubstituted heterocycle fused gamma-carboline compounds (the compoundsdescribed herein below), either alone or as an adjunctive therapy forthe treatment of residual symptoms of psychosis, particularlyschizophrenia. This is a new and unexpected utility.

Thus, the present invention is directed to a method (Method A) for thetreatment of residual symptoms comprising administering to a patient inneed thereof an effective amount of the Compound of Formula I:

wherein:

-   -   X is —O—, —NH— or —N(CH₃)—;    -   Y is —O—, —C(R₂)(OH)—, —C(R₃)(OR₁) or —C(O)—;    -   R₁ is C₁₋₆alkyl (e.g., methyl) or a physiologically hydrolysable        and acceptable acyl, e.g., selected from —C(O)—C₁₋₂₁alkyl (e.g.,        —C(O)—C₁₋₅alkyl, —C(O)—C₆₋₁₅alkyl or —C(O)—C₁₆₋₂₁alkyl), for        example wherein R₁ is —C(O)—C₆alkyl, —C(O)—C₇alkyl,        —C(O)—C₉alkyl, —C(O)—C₁₁alkyl, —C(O)—C₁₃alkyl, or —C(O)—C₁₅alkyl        e.g., wherein such compound hydrolyzes to provide a natural or        unnatural, saturated or unsaturated fatty acid of formula R₁—OH        and a Compound of Formula 1 wherein Y is —C(R₂)(OH)—, e.g.,        wherein the compound hydrolyzes to form the hydroxy Compound of        Formula I wherein Y is —C(R₂)(OH)— on the one hand and octanoic        acid, decanoic acid, dodecanoic acid, tetradecanoic acid or        hexadecanoic acid on the other hand);    -   R₂ is H or —C₁₋₆alkyl (e.g., methyl); and    -   R₃ is H or —C₁₋₆alkyl (e.g., methyl);    -   e.g., wherein “alkyl” refers to a straight chain hydrocarbon        moiety, optionally saturated or unsaturated and optionally        substituted with one or more hydroxy or C₁₋₂₂alkoxy (e.g.,        ethoxy) groups;        in free or pharmaceutically acceptable salt form.

In a further embodiment, the compound of Formula I of Method A is acompound wherein:

-   -   X is —O—, —NH— or —N(CH₃)—;    -   Y is —O—, —C(H)(OH)—, —C(H)(OR₁) or —C(O)—; and    -   R₁ is a physiologically hydrolysable and acceptable acyl, e.g.,        selected from —C(O)—C₁₋₂₁alkyl (e.g., —C(O)—C₁₋₅alkyl,        —C(O)—C₆₋₁₅alkyl or —C(O)—C₁₆₋₂₁alkyl), for example wherein R₁        is —C(O)—C₆alkyl, —C(O)—C₇alkyl, —C(O)—C₉alkyl, —C(O)—C₁₁alkyl,        —C(O)—C₁₃alkyl, or —C(O)—C₁₅alkyl e.g., wherein such compound        hydrolyzes to provide a natural or unnatural, saturated or        unsaturated fatty acid of formula R₁—OH and a Compound of        Formula I wherein Y is —C(R₂)(OH)—, e.g., wherein the compound        hydrolyzes to form the hydroxy Compound of Formula I wherein Y        is —C(R₂)(OH)— on the one hand and octanoic acid, decanoic acid,        dodecanoic acid, tetradecanoic acid or hexadecanoic acid on the        other hand);    -   e.g., wherein “alkyl” refers to a straight chain hydrocarbon        moiety, optionally saturated or unsaturated and optionally        substituted with one or more hydroxy or C₁₋₂₂alkoxy (e.g.,        ethoxy) groups;

in free or pharmaceutically acceptable salt form.

In a further embodiment, the patient of Method A is suffering fromresidual symptoms of psychosis, for example, schizophrenia (e.g.,residual sub-type), delusional disorder (e.g., somatic type), majordepression with psychosis, bipolar disorder with psychotic symptoms,brief psychotic disorder, schizophreniform disorder, schizoaffectivedisorder or psychosis caused by a medical condition or substance use.Preferably, the patient is suffering from residual symptoms ofschizophrenia.

In another further embodiment, the residual phase symptoms include:negative symptoms such as blunted affect, emotional withdrawal, poorrapport, passive or apathetic social withdrawal, difficulty in abstractthinking, lack of spontaneity and flow of conversation and stereotypedthinking; general psychopathology symptoms such as somatic concern,anxiety, guilt feelings, tension, mannerisms and posturing, depression,motor retardation, uncooperativeness, unusual thought content,disorientation, poor attention, lack of judgment and insight,disturbance of volition, poor impulse control, preoccupation and activesocial avoidance; cognitive impairment and sleep disorders (e.g.,insomnia). In a particular embodiment, Method A treats residual symptoms(negative, effective and cognitive symptoms) associated withschizophrenia.

In another further embodiment, the effective amount of the Compound ofFormula I is about 1 mg to about 140 mg per dose per day, in anotherembodiment, about 2.5 mg to about 120 mg, in another embodiment about 10mg to about 120 mg per dose per day, in another embodiment, about 60 mgto about 120 mg per dose per day, in still another embodiment, about 10mg to about 60 mg per dose per day, in another embodiment, about 20 mgto about 60 mg per dose per day, in still another embodiment, about 20mg, about 40 mg, or about 60 mg per dose per day. The compounds of thecurrent invention are effective in treating both the positive symptoms,which occur during active or acute phase of psychosis (e.g., effectivein treating positive symptoms such as delusions and hallucinations) aswell as negative and other residual symptoms generally observed in theresidual phase. Preferably, the effective amount for the treatment ofacute and residual symptoms of schizophrenia is about 60 mg per day. Inparticular embodiment, the dosages disclose herein for oraladministration are based on the amount of the Compounds of Formula I inacid addition salt form, particularly toluene sulfonic acid additionsalt form.

Therefore, the Invention Provides Methods as Follows:

-   -   1.1 Method A comprising a compound of Formula I, wherein X is        —N(CH₃);    -   1.2 Method A comprising a compound of Formula I, wherein X is        —NH;    -   1.3 Method A comprising a compound of Formula I, wherein X is O;    -   1.4 Method A or any of 1.1-1.3, comprising a compound of Formula        I, wherein Y is —C(O)—;    -   1.5 Method A or any of 1.1-1.3, comprising a compound of Formula        I, wherein Y is —O—;    -   1.6 Method A or any of 1.1-1.3 comprising a compound of Formula        I, wherein Y is —C(R₂)(OH)—, e.g., —C(H)(OH)—;    -   1.7 Method A or any of 1.1-1.3 comprising a compound of Formula        I, wherein Y is-C(R₃)(OR₁), e.g., —C(H)(OR₁);    -   1.8 Method A or formula 1.7, wherein R₁ is —C(O)—C₁₋₂₁alkyl        (e.g., —C(O)—C₁₋₅alkyl, —C(O)—C₆₋₁₅alkyl or —C(O)—C₁₆₋₂₁alkyl),        preferably said alkyl is a straight chain, optionally saturated        or unsaturated and optionally substituted with one or more        hydroxy or C₁₋₂₂alkoxy (e.g., ethoxy) groups, for example R₁ is        —C(O)—C₆alkyl, —C(O)—C₇alkyl, —C(O)—C₉alkyl, —C(O)—C₁₁alkyl,        —C(O)—C₁₃alkyl or —C(O)—C₁₅alkyl wherein such compound        hydrolyzes to form the residue of a natural or unnatural,        saturated or unsaturated fatty acid, e.g., the compound        hydrolyzes to form the hydroxy compound on the one hand and        octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic        acid or hexadecanoic acid on the other hand);    -   1.9 Method A or formula 1.7, wherein R₁ is —C(O)—C₆₋₁₅alkyl,        e.g., —C(O)—C₉alkyl;    -   1.10 Method A or formula 1.7, wherein R₁ is —C(O)—C₁₋₅alkyl,        e.g., —C(O)—C₃alkyl;    -   1.11 Method A or formula 1.7, wherein R₁ is —C₁₋₆alkyl (e.g.,        methyl);    -   1.12 Method A or any of formula 1.1-1.11, wherein R₂ is H or        —C₁₋₆alkyl (e.g., methyl);    -   1.13 Method A or any of formula 1.1-1.11, wherein R₂ is H;    -   1.14 Method A or any of formula 1.1-1.11, wherein R₂ is        —C₁₋₆alkyl (e.g., methyl);    -   1.15 Method A or any of formula 1.1-1.11, wherein R₃ is H or        —C₁₋₆alkyl (e.g., methyl);    -   1.16 Method A or any of formula 1.1-1.11, wherein R₃ is H;    -   1.17 Method A or any of formula 1.1-1.11, wherein R₃ is        —C₁₋₆alkyl (e.g., methyl);    -   1.18 any of the preceding methods wherein the Compound of        Formula I is selected from a group consisting of a compound of        Formula I wherein:        -   X is —O— and Y is —C(H)(OH)—,        -   X is —NH— and Y is —C(H)(OH)—,        -   X is —N(CH₃)— and Y is —C(H)(OH)—,        -   X is —O— and Y is —C(O)—,        -   X is —O— and Y is —O—,        -   X is —N(CH₃)— and Y is —C(O)—,        -   X is —N(CH₃)— and Y is —O—,        -   X is —NH— and Y is —C(O)—,        -   X is —NH— and Y is —O—,        -   X is —N(CH₃)— and Y is —C(H)(OR₁),        -   X is —NH— and Y is —C(H)(OR₁), or        -   X is —O— and Y is —C(H)(OR₁);        -   X is —O— and Y is —C(CH₃)(OH)—,        -   X is —NH— and Y is C(CH₃)(OH)—,        -   X is —N(CH₃)— and Y is C(CH₃)(OH)—,    -   1.19 any of the preceding methods wherein X is —O— and Y is        —C(O)— in the Compound of Formula I;    -   1.20 any of the preceding methods wherein X is —NH— and Y is        —C(H)(OH)— in the Compound of Formula I;    -   1.21 any of the preceding methods wherein X is —N(CH₃)— and Y is        —C(H)(OH)— in the Compound of Formula I is;    -   1.22 any of the preceding methods wherein X is —O— and Y is        —C(O)— in the Compound of Formula I;    -   1.23 any of the preceding methods wherein X is —O— and Y is —O—        in the Compound of Formula I;    -   1.24 any of the preceding methods wherein X is —N(CH₃)— and Y is        —C(O)— in the Compound of Formula I;    -   1.25 any of the preceding methods wherein X is —O— and Y is        —C(H)(OH)— in the Compound of Formula I    -   1.26 any of the preceding methods wherein X is —NH— and Y is        —C(H)(OH)— in the compound of Formula I;    -   1.27 any of the preceding methods wherein X is —N(CH₃)— and Y is        —C(H)(OH)— in the compound of Formula I;    -   1.28 any of the preceding methods wherein X is —N(CH₃)— and Y is        —C(H)(OR₁) and R₁ is —C(O)—C₁₋₂₁alkyl in the compound of Formula        I;    -   1.29 any of the preceding methods wherein X is —N(H)— and Y is        —C(H)(OR₁) and R₁ is —C(O)—C₁₋₂₁alkyl in the compound of Formula        I;    -   1.30 any of the preceding methods wherein X is —O— and Y is        —C(H)(OR₁) and R₁ is —C(O)—C₁₋₂₁alkyl in the compound of Formula        I;    -   1.31 Any of the preceding methods, wherein the Compound of        Formula I is a compound of Formula IA:

-   -   1.32 Any of the preceding methods, wherein the Compound of        Formula I is a compound of Formula IB:

-   -   1.33 Any of the preceding methods, wherein the Compound of        Formula I is a compound of Formula IC:

-   -   1.34 Any of the preceding methods, wherein the Compound of        Formula I is a compound of Formula ID (sometimes referred to        herein as Compound B):

-   -   1.35 Any of the preceding methods, wherein the Compound of        Formula I is a compound of Formula IE (sometimes referred to        herein as Compound A):

-   -   1.36 Any of the preceding methods, wherein the Compound of        Formula I is a compound of Formula IF:

-   -   1.37 Any of the preceding methods, wherein the Compound of        Formula I is a compound of Formula IG:

-   -   1.38 Any of the foregoing methods wherein the Compound of        Formula I is administered orally, for example in once a day in a        single daily dose or twice a day in a divided dose, for example        in the form of a tablet or capsule.    -   1.39 Any of the foregoing methods wherein the effective amount        of the Compound of Formula I is a daily oral dosage of 10-120        mg/day, e.g., about 60 mg of the p-toluene sulfonic acid        addition salt of the Compound of Formula IE:

-   -   1.40 Any of the foregoing methods wherein the Compound of        Formula I is administered as a sustained release injectable        form, e.g., an injectable depot form, e.g., administered once or        twice a month, e.g., in the form of a bioerodable microparticle,        e.g., the Compound of Formula IE:

-   -   -   e.g., in free base form.

    -   1.41 Any of the foregoing methods comprising administering a        long acting injectable formulation of a Compound of Formula I,        e.g., Composition 2, e.g., any of Compositions 2.1, et seq. as        set forth below.

    -   1.42 Any of the foregoing methods further comprising        administering one or more other therapeutic agents such as        additional antipsychotic agents and/or anti-depressive agents        and/or hypnotic agents;

    -   1.43 Method 1.38, wherein the one or more other therapeutic        agents are selected from anti-depressive agents such as        compounds that modulate GABA activity (e.g., enhances the        activity and facilitates GABA transmission), a GABA-B receptor        agonist, a 5-HT modulator (e.g., a 5-HT_(1A) receptor agonist, a        5-HT_(2A) receptor antagonist, a 5-HT_(2A) receptor inverse        agonist, etc.), a melatonin receptor agonist, an ion channel        modulator (e.g., blocker), a serotonin-2 receptor        antagonist/reuptake inhibitor (SARIs), an orexin receptor        antagonist, an H3 receptor agonist, a noradrenergic receptor        antagonist, a galanin receptor agonist, a CRH receptor        antagonist, human growth hormone, a growth hormone receptor        agonist, estrogen, an estrogen receptor agonist, a neurokinin-1        drug; and antipsychotic agents, e.g., atypical antipsychotic        agents, in free or pharmaceutically acceptable salt form;

    -   1.44 Method 1.42 or 1.43, wherein the one or more other        therapeutic agents are antipsychotic agents, e.g.,        chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine,        mesoridazine molindone, perphenazine, pimozide, prochlorperazine        promazine, thioridazine, thiothixene, trifluoperazine,        clozapine, aripiprazole, olanzapine, quetiapine, risperidone,        ziprasidone, paliperidone, asenapine, lurasidone, iloperidone,        cariprazine, amisulpride, zotepine, sertindole, wherein the one        or more other therapeutic agents are administered as an adjunct        to the compound of Formula I or the compound of Formula I is an        adjunct to the one or more other therapeutic agents;

    -   1.45 Any of the foregoing methods, wherein the effective amount        is 1 mg to 120 mg per day or 10 mg to 120 mg per day, or 10 mg        to 60 mg per day, or 10 mg to 40 mg per day, or 1 mg to 10 mg        per day, or 10 mg per day, 20 mg per day, 40 mg per day or 60 mg        per day; In a particular embodiment, the effective amount of the        Compound of Formula I disclosed in this formula is based on the        amount of the Compound of Formula I in an acid addition salt,        non-prodrug form, e.g., in toluenesulfonic acid addition salt,        non-prodrug form.

    -   1.46 Method A or any of 1.38-1.45, wherein the one or more other        therapeutic agents are anti-depressive agents, e.g., one or more        antidepressants selected from selective serotonin reuptake        inhibitors (SSRIs)(e.g., selected from citalopram, escitalopram        oxalate, fluoxetine, fluvoxamine maleate, paroxetine,        sertraline, dapoxetine), serotonin-norepinephrine reuptake        inhibitors (SNRIs)(e.g., selected from venlafaxine,        desvenlafaxine, duloxetine, milnacipran, levomilnacipran,        sibutramine), and tricyclic antidepressants; triple reuptake        inhibitors, anxiolytics, busperone, and trazadone;

    -   1.47 Methods 1.45 wherein compound of Formula I is administered        as an adjunct to one or more other therapeutic agents such as        SSRI anti-depressive agents or the SSRI anti-depressive agents        are administered as an adjunct to the compound of Formula I;

    -   1.48 The method of 1.47, wherein said one or more antidepressant        agents are selected form SSRI's such as citalopram (Celexa,        Cipramil, Emocal, Sepram, Seropram), escitalopram oxalate        (Lexapro, Cipralex, Esertia), fluoxetine (Prozac, Fontex,        Seromex, Seronil, Sarafem, Fluctin (EUR)), fluvoxamine maleate        (Luvox, Faverin), paroxetine (Paxil, Seroxat, Aropax, Deroxat,        Paroxat), sertraline (Zoloft, Lustral, Serlain), dapoxetine;        -   in free or pharmaceutically acceptable salt form;

    -   1.49 Any of the foregoing methods, wherein the compound of        Formula I is administered as part of a long-acting injectable        microsphere composition;

    -   1.50 The method of 1.49, wherein the long-acting injectable        microsphere composition is a composition according to any one of        2.1 to 2.22 herein below.

In a particular embodiment of Method A et seq., the patient is a patientwho has not responded or has not responded adequately to treatment withanother antipsychotic agent, e.g., chlorpromazine, haloperidol,droperidol, fluphenazine, loxapine, mesoridazine molindone,perphenazine, pimozide, prochlorperazine promazine, thioridazine,thiothixene, trifluoperazine, clozapine, aripiprazole, olanzapine,quetiapine, risperidone, ziprasidone, paliperidone, asenapine,lurasidone, iloperidone, cariprazine, amisulpride, zotepine, sertindole.Therefore, the compound of Formula I may be administered as a primarytherapy or an adjunct therapy, e.g., adjunct to another antipsychoticagent.

In another aspect, the invention provides a method (Method B) for thetreatment of any of the following disorders: schizoaffective disorder,co-morbid depression, major depressive disorder, bipolar disorder (e.g.,bipolar I and/or bipolar II disorder), Autism Spectrum disorder (e.g.,autistic disorder, Asperger's disorder, Pervasive developmental disordernot otherwise specified (PDD-NOS), Rett's disorder (Rett syndrome),childhood disintegrative disorder) comprising administering to a patientin need thereof an effective amount of a Compound of Formula I, in freeor pharmaceutically acceptable salt form. In a particular embodiment,the disorder of Method B is bipolar disorder (e.g., bipolar I and/orbipolar II disorder). In another particular embodiment, the disorder ofMethod B is Autism Spectrum disorder. In still another particularembodiment, the disorder of Method B is major depressive disorder.

Therefore, depending on the combination of disorders to be treated, theCompounds of Formula I may be used strategically. For example at lowerdoses (for example, a daily oral dose of 1-10 mg, e.g., 1 mg, 5 mg and10 mg of the Compound of Formula I in toluenesulfonic acid addition saltform), the Compounds of Formula I are useful for the treatment of sleepdisorder, aggression and agitation, Alzheimer's disease and otherdementias, Autism Spectrum disorder, Parkinson's disease andIntermittent Explosive Disorder (IED). At higher dose (for example, adaily oral dose of 60 mg of the Compound of Formula I in toluenesulfonicacid addition salt form), the Compounds of Formula I are useful fortreating acute exacerbated and residual schizophrenia, bipolardepression, major depressive disorder, generalized anxiety disorder. Atvery high dose (for example a daily oral dose of 120 mg of the Compoundof Formula I in toluenesulfonic acid addition salt form), morningadministration may produce somnolence/sedation. Therefore, at suchhigher daily doses, administration in the evening is preferable.

The Compounds of Formula I may exist in free or salt form, e.g., as acidaddition salts. In this specification unless otherwise indicatedlanguage such as “Compounds of Formula I”, “antipsychotic agents”,“anti-depressive agents”, “other therapeutic agents”, and the like is tobe understood as embracing the compounds in any form, for example freeor acid addition salt form, or where the compounds contain acidicsubstituents, in base addition salt form. The Compounds of Formula I areintended for use as pharmaceuticals, therefore pharmaceuticallyacceptable salts are preferred. Salts which are unsuitable forpharmaceutical uses may be useful, for example, for the isolation orpurification of free Compounds of Formula I or their pharmaceuticallyacceptable salts, are therefore also included. Pharmaceuticallyacceptable salts include, for example, the hydrochloride, mesylate andtosylate salts. Preferably, the Compounds of Formula I, particularlywherein X is —N(CH₃)— and Y is —C(O)—, are in tosylate (toluenesulfonicacid addition) salt form. Where dosage amounts of salts are given byweight, e.g., milligrams per day or milligrams per unit dose, the dosageamount of the salt may be based on the weight of the corresponding freebase or as otherwise indicated. In a particular embodiment, the dosageof the Compounds of Formula I in acid addition salt form for oraladministration is based on the weight of the toluenesulfonic acidaddition salt form, not the free base form. For example, in a particularembodiment, the 10 mg, 60 mg, 120 mg dosage amount of the Compound ofFormula I is based respectively, on 10 mg, 60 mg and 120 mg of theCompound of Formula I in toluenesulfonic acid addition salt form, notbased on the amount of the free base. For example, 60 mg dosage of thecompound for oral administration of Compounds of Formula I (e.g.,wherein X is —N(CH₃)— and Y is —C(O)—) in toluene sulfonic acid additionsalt form refers to the compound in tosylate salt form, which isequivalent to approximately 41.7 mg of said compound in free base form.

The invention also provides the foregoing methods, e.g., Method A, e.g.,any of 1.1-1.50, and Method B, wherein the Compound of Formula I, infree or pharmaceutically acceptable salt form is administered in acomposition, wherein said Compound of Formula I in free orpharmaceutically acceptable salt form is in admixture or in associationwith a pharmaceutically acceptable diluent or carrier.

In a particular embodiment, the invention also provides the foregoingmethods, e.g., Method A, e.g., any of 1.1-1.50, and Method B, whereinthe Compound of Formula I, in free or pharmaceutically acceptable saltform is administered in an immediate release or sustained or delayedrelease formulation, e.g., depot formulation.

In one embodiment, the sustained or delayed release formulationcomprises the Compounds of Formula I disclosed herein (e.g., thecompound of formula I or any of those described in any of formulae1.1-1.50) in a polymeric matrix. In another embodiment, the Compounds ofFormula I are dispersed or dissolved within the polymeric matrix. In afurther embodiment, the polymeric matrix comprises standard polymersused in depot formulations such as polymers selected from a polyester ofa hydroxy fatty acid and derivatives thereof, or a polymer of an alkylalpha-cyanoacrylate, a polyalkylene oxalate, a poly(ortho) ester, apolycarbonate, a polyortho-carbonate, a polyamino acid, a hyaluronicacid ester, and mixtures thereof. In a further embodiment, the polymeris selected from a group consisting of polylactide, poly d,l-lactide,poly glycolide, PLGA 50:50, PLGA 75:25, PLGA 85:15 and PLGA 90:10polymer. In another embodiment, the polymer is selected frompoly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid,copolymers of the foregoing, poly(aliphatic carboxylic acids),copolyoxalates, polycaprolactone, polydioxonone, poly(ortho carbonates),poly(acetals), poly(lactic acid-caprolactone), polyorthoesters,poly(glycolic acid-caprolactone), polyanhydrides, and natural polymersincluding albumin, casein, and waxes, such as, glycerol mono- anddistearate, and the like. In a particular embodiment, the polymericmatrix comprises poly (d,l-lactide-co-glycolide). The Compound ofFormula I in a polymeric matrix may be in admixture or in associationwith a pharmaceutically acceptable diluent or carrier.

The sustained or delayed release formulations as hereinbefore describedare particularly useful for sustained or delayed release, wherein theCompounds of Formula I are released upon degradation of the polymericmatrix. These formulations may release the Compounds of Formula I over aperiod of up to 180 days, e.g., from about 14 to about 30 to about 180days. For example, the polymeric matrix may degrade and release theCompounds of Formula I over a period of about 30, about 60 or about 90days. In another example, the polymeric matrix may degrade and releasethe Compounds of Formula I over a period of about 120, or about 180days.

In still another further embodiment, the sustained or delayed releaseformulation is formulated for administration by injection.

For example, the disclosure provides long-acting injectable (LAI)formulations of Compounds of Formula I. Such LAIs may be optimized as tocarrier composition, particle size, molecular weight of carrier, loadingof active ingredient, and dosage, e.g., as described in the examples. Inaddition to convenience of administration, and ensuring patientcompliance, LAI formulations of Compounds of Formula I surprisinglyprovide advantages as to pharmacokinetics and side effects. When aCompound of Formula I is administered using an LAI formulation, asopposed to an oral dosage form, the first pass metabolism in the liveris avoided, meaning that a lower proportion of Compound of Formula I ismetabolized before reaching the brain. Sustained or delayed releaseformulations as described herein generally impart fewer extrapyramidalside effects, and offer better tolerability and reduced total dose thanthe corresponding immediate release formations. Sustained or delayedrelease formulations, and particularly long-acting injectableformulations, allow a patient to achieve and maintain therapeuticallyeffective levels of drug in the CNS while receiving a much lower totaldosage than would be needed to achieve the same body level of drug usingimmediate release oral formulations. For long-acting injectableformulations in particular, this effect is partly due to the avoidanceof the first-pass metabolism that occurs with oral medications,including oral sustained and delayed release medications.

The effective amount of the Compound of Formula I when administered as along-acting injectable formulation is therefore found to be much lowerthan the effective amount when administered orally, e.g., from about 100mg per month to about 600 mg per month, and preferably from 150 mg permonth to 300 mg per month.

In a particular embodiment, therefore, the disclosure provides along-acting injectable formulation (Composition 2) comprising polymericmicrospheres, wherein the microspheres comprise:

-   -   a poly(D,L-lactide-co-glycolide) polymer (PLGA) polymer matrix        and an effective amount of a Compound of Formula I, as        hereinbefore described, in free or pharmaceutically acceptable        salt form, the Compound of Formula I being dispersed, dissolved        or encapsulated in the polymer matrix.        For example, the disclosure provides:    -   2.1 Composition 2, wherein the PLGA polymer is about 75:25        PLA/PLG with either carboxylic acid or carboxylic ester end        groups.    -   2.2 Composition 2 or 2.1, wherein the PLGA polymer is about        75:25 PLA/PLG with carboxylic acid end groups.    -   2.3 Composition 2, 2.1 or 2.2, wherein the Compound of Formula I        is in free base form.    -   2.4 Any foregoing Composition wherein the Compound of Formula I        is selected from Compounds of Formula IA, IB, IC, ID, IE.    -   2.5 Any foregoing Composition wherein the Compound of Formula I        is the Compound of Formula IE:

-   -   -   e.g., in free base form.

    -   2.6 Any of the foregoing Compositions, wherein the Compound of        Formula I is a compound of Formula ID:

-   -   -   e.g., in free base form.

    -   2.7 Any foregoing Composition wherein the average molecular        weight range for the PLGA polymer is, for example 20 kD to 200        kD, for example, 24,000 to 38,000 daltons, or about 113,000        daltons or about 159,000 daltons.

    -   2.8 Any foregoing Composition wherein the time frame for        complete degradation of the microspheres and release of the        encapsulated drug compounds is, e.g., less than 6 months, less        than 4 months, less than 3 months, less than 2 months, or less        than 1 month.

    -   2.9 Any foregoing Composition wherein the diameter of the        microspheres, e.g., the average diameter (or D₅₀), the 10^(th)        percentile diameter (D₁₀), the 25^(th) percentile diameter        (D₂₅), the 75^(th) percentile diameter (D₇₅), or the 90^(th)        percentile diameter (D₉₀), is from about 10 μm to about 200 μm,        for example, from about 20 μm to about 160 μm, or from about 20        μm to about 120 μm, or from about 20 μm to about 100 μm, or from        about 20 μm to about 80 μm, or from about 20 μm to about 70 μm,        or from about 20 μm to about 60 μm, or from about 20 μm to about        50 μm, or from about 20 μm to about 40 μm, or from about 20 μm        to about 30 μm, or from about 25 μm to about 70 μm, or from        about 25 μm to about 60 μm, or from about 25 μm to about 50 μm,        or from about 25 μm to about 40 μm, or from about 30 μm to about        60 μm, or from about 30 to 50 μm, or from about 30 μm to about        40 μm, or from about 30 μm to about 120 μm, or from about 40 μm        to about 120 μm, or from about 40 μm to about 100 μm, or from        about 40 μm to about 80 μm, or from about 40 μm to about 70 μm,        or from about 40 μm to about 60 μm, or from about 40 μm to about        50 μm, or from about 50 μm to about 100 μm, or from about 50 μm        to about 80 μm, or from about 50 μm to about 70 μm, or from        about 50 μm to about 60 μm, or from about 60 μm to about 100 μm,        or from about 60 μm to about 90 μm, or from about 60 μm to about        80 μm, or from about 60 μm to about 70 μm, or from about 70 μm        to about 100 μm, or from about 70 μm to about 90 μm, or from        about 70 μm to about 80 μm, or from about 75 μm to about 110 μm,        or from about 40 μm to about 160 μm, or from about 50 μm to        about 160 μm, or from about 50 μm to about 120 μm, or about 20        μm, about 30 μm, about 40 μm, about 50 μm, about 60 μm, about 70        μm, about 80 μm, about 90 μm, or about 100 μm.

    -   2.10 Any foregoing Composition wherein the diameter of the        microspheres, e.g., the average diameter (or D₅₀), the 10^(th)        percentile diameter (D₁₀), the 25^(th) percentile diameter        (D₂₅), the 75^(th) percentile diameter (D₇₅), or the 90^(th)        percentile diameter (D₉₀), is from 10 μm to 160 μm, for example,        20 μm to 70 μm, 25 μm to 70 μm, 40 to 120 μm, or 20 μm to 60 μm,        or 20 μm to 50 μm, 30 μm to 60 μm, 30 to 50 μm, 40 μm to 50 μm,        or about 30 μm, or about 40 μm, or about 50 μm.

    -   2.11 Any foregoing Composition wherein the amount of the        Compound of Formula I dispersed, dissolved or encapsulated in        each microsphere, on average, is from about 5% by weight to        about 50% by weight, for example, from about 10% by weight to        about 50% by weight, or from about 20% by weight to about 40% by        weight, or from about 30% by weight to about 40% by weight, or,        for example, about 8.5% by weight, or about 16% by weight, or        about 30% by weight, or about 35% by weight, or about 40% by        weight.

    -   2.12 Any foregoing Composition wherein the inherent viscosity is        about 0.1 to about 1, for example about 0.3 to about 0.4, about        0.7, about 0.8, about 0.9 dL/g.

    -   2.13 Any of the foregoing Compositions for use in Method A, e.g.        any of Methods 1.1 et seq. or in Method B, as hereinbefore        described.

    -   2.14 Any of the foregoing Compositions for use in patients who        have difficulty adhering to a regular treatment regimen, either        intentionally or unintentionally.

    -   2.15 Any of the foregoing Compositions for administration to        patients on a weekly, biweekly or monthly basis, or once every        2, 3 4, 5 or 6 months.

    -   2.16 Any of the foregoing Compositions for intramuscular,        intraperitoneal, intrathecal, epidural, or subcutaneous        injection, e.g. subcutaneous or intramuscular injection, e.g.,        intramuscular injection.

    -   2.17 Any of the foregoing Compositions for intramuscular        injection.

    -   2.18 Any of the foregoing Compositions, further comprising an        antioxidant, e.g., in an amount effective to inhibit or reduce        oxidation of the Compound of Formula 1.

    -   2.19 Any of the foregoing Compositions further comprising an        antioxidant, wherein the antioxidant is a water-soluble        antioxidant (e.g., ascorbic acid, lipoic acid), or a        lipid-soluble antioxidant (e.g., lipoic acid, vitamin E,        tocopherols, carotenes or phenolic antioxidants), or a neutral        or weakly basic antioxidant, or a catalytic antioxidant (e.g.,        ebselen), or a metal-containing antioxidant.

    -   2.20 Any of the foregoing Compositions further comprising an        antioxidant, wherein the antioxidant is a lipidic or neutral or        weakly basic antioxidants, e.g., wherein the polymer comprises        carboxy end groups.

    -   2.21 Any of the foregoing Compositions, further comprising an        antioxidant, wherein the anti-oxidant is a phenolic antioxidant        (e.g., butylated hydroxyanisole (BHA) or butylated        hydroxytoluene (BHT)).

    -   2.22 Any of the foregoing Compositions, further comprising an        antioxidant, wherein the anti-oxidant is BHT.

In still another embodiment, the invention provides Methods A or B ashereinbefore described wherein the Compound of Formula I is formulatedin an osmotic controlled release oral delivery system (OROS) fordelivery of the Compounds of Formula I, e.g., analogous to the systemsdescribed in WO 2000/35419 and EP 1 539 115 (U.S. Pub. No.2009/0202631), the contents of each of which applications areincorporated by reference in their entirety. Therefore in oneembodiment, the invention provides Methods A or B as hereinbeforedescribed, wherein the compound of Formula I is formulated in a devicecomprising (a) a gelatin capsule containing the Compound of Formula I,in free or pharmaceutically acceptable salt form, as hereinbeforedescribed; (b) a multilayer wall superposed on the gelatin capsulecomprising, in outward order from the capsule: (i) a barrier layer, (ii)an expandable layer, and (iii) a semipermeable layer; and (c) andorifice formed or formable through the wall. (Composition P.1)

In still another embodiment, the invention provides Methods A or B ashereinbefore described wherein the compound of Formula I is formulatedin a composition comprising a gelatin capsule containing a liquid, theCompounds of Formula I, in free or pharmaceutically acceptable salt formas hereinbefore described, the gelatin capsule being surrounded by acomposite wall comprising a barrier layer contacting the externalsurface of the gelatin capsule, an expandable layer contacting thebarrier layer, a semi-permeable layer encompassing the expandable layer,and an exit orifice formed or formable in the wall. (Composition P.2)

In still another embodiment, the invention provides Methods A or B ashereinbefore described wherein the compound of Formula I is formulatedin a composition comprising a gelatin capsule containing a liquid, theCompound of Formula I, in free or pharmaceutically acceptable salt formas hereinbefore described, the gelatin capsule being surrounded by acomposite wall comprising a barrier layer contacting the externalsurface of the gelatin capsule, an expandable layer contacting thebarrier layer, a semipermeable layer encompassing the expandable layer,and an exit orifice formed or formable in the wall, wherein the barrierlayer forms a seal between the expandable layer and the environment atthe exit orifice. (Composition P.3)

In still another embodiment, the invention provides a compositioncomprising a gelatin capsule containing a liquid, the Compound ofFormula I, in free or pharmaceutically acceptable salt form ashereinbefore described, the gelatin capsule being surrounded by abarrier layer contacting the external surface of the gelatin capsule, anexpandable layer contacting a portion of the barrier layer, asemi-permeable layer encompassing at least the expandable layer, and anexit orifice formed or formable in the dosage form extending from theexternal surface of the gelatin capsule to the environment of use.(Composition P.4). The expandable layer may be formed in one or morediscrete sections, such as for example, two sections located on opposingsides or ends of the gelatin capsule.

In a particular embodiment, the Compounds of Formula I in theOsmotic-controlled Release Oral delivery System (i.e., in CompositionP.1-P.4) as hereinbefore described are in a liquid formulation, whichformulation may be neat, liquid active agent, liquid active agent in asolution, suspension, emulsion or self-emulsifying composition or thelike.

Further information on Osmotic-controlled Release Oral delivery Systemcompositions including characteristics of the gelatin capsule, barrierlayer, expandable layer, semi-permeable layer, and orifice may be foundin WO 2000/35419, the contents of which are incorporated by reference intheir entirety. Other Osmotic-controlled Release Oral delivery Systemsmay be found in EP 1 539 115 (U.S. Pub. No. 2009/0202631), the contentsof which are incorporated by reference in their entirety.

In still another embodiment, the invention provides Methods A or B ashereinbefore described wherein the compound of formula I is formulatedin a device comprising (a) two or more layers, said two or more layerscomprising a first layer and a second layer, said first layer comprisingthe Compound of Formula I, in free or pharmaceutically acceptable saltform as herein before described, said second layer comprising a polymer;(b) an outer wall surrounding said two or more layers; and (c) anorifice in said outer wall. (Composition P.5)

Composition P.5 preferably utilizes a semi-permeable membranesurrounding the three-layer-core described herein: in these embodimentsthe first layer is referred to as a first drug layer and contains lowamounts of drug (e.g., the Compounds of Formula I) and an osmotic agentsuch as a salt, the middle layer referred to as the second drug layercontains higher amounts of drug, excipients and no salt; and the thirdlayer referred to as the push layer contains osmotic agents and no drug.At least one orifice is drilled through the membrane on the first druglayer end of the capsule-shaped tablet. (Composition P.6)

Composition P.5 or P.6 may comprise a membrane defining a compartment,the membrane surrounding an inner protective subcoat, at least one exitorifice formed or formable therein and at least a portion of themembrane being semi-permeable; an expandable layer located within thecompartment remote from the exit orifice and in fluid communication withthe semi-permeable portion of the membrane; a first drug layer locatedadjacent to the exit orifice; and a second drug layer located within thecompartment between the first drug layer and the expandable layer, thedrug layers comprising the Compound of Formula I in free orpharmaceutically acceptable salt thereof. Depending upon the relativeviscosity of the first drug layer and second drug layer, differentrelease profiles are obtained. It is imperative to identify the optimumviscosity for each layer. In the present invention, viscosity ismodulated by addition of a salt, e.g., sodium chloride. The deliveryprofile from the core is dependent on the weight, formulation andthickness of each of the drug layers. (Composition P.7)

In a particular embodiment, Composition P.7 comprises the first druglayer comprising salt and the second drug layer containing no salt.Composition P.5-P.7 may optionally comprise a flow-promoting layerbetween the membrane and the drug layers. Compositions P.1-P.7 willgenerally be referred to as Osmotic-controlled Release Oral deliverySystem Composition.

The invention further provides a pharmaceutical composition ashereinbefore described comprising a Compound of Formula I in free orpharmaceutically acceptable salt form, e.g., as described in any ofMethods A or 1.1-1.50, or Method B in admixture with a pharmaceuticallyacceptable diluent or carrier, e.g., in an immediate or sustained ordelayed release formulation, including a long-acting injectableformulation, for use in the treatment of residual symptoms as describedin any of Methods A, or 1.1-1.50, or for use in the treatment of thedisorders as described in Method B.

In another aspect, the invention provides use of the Compound of FormulaI or the pharmaceutical composition comprising the compound of Formula Iin free or pharmaceutically acceptable salt form as described in MethodsA or 1.1-1.50, formulated in an immediate release or sustained ordelayed release formulation, including a long-acting injectableformulation, as hereinbefore described, (in the manufacture of amedicament) for the treatment of residual symptoms as described in anyof Methods A or 1.1-1.50, or for the treatment of the disorders asdescribed in Method B.

In another aspect, the invention provides use of the Compound of FormulaI or any pharmaceutical composition as hereinbefore described (e.g.,Compositions P.1 to P.7 or Composition 2) comprising the Compound ofFormula I in free or pharmaceutically acceptable salt form as describedin Methods A or 1.1-1.50, wherein the compound is in admixture orassociation with an antioxidant. Without being bound by any particulartheory, it is believed that the presence of an antioxidant within thecomposition will stabilize the compound of Formula I. In a preferredembodiment, the long acting injectable microspheres contain anantioxidant, wherein it is believed that the antioxidant will stabilizethe compound of Formula I during release from the microsphere.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: PANSS Negative Symptom Sub-Scale for patient subgroup withprominent negative symptoms at baseline.

FIG. 2: Total PANSS in sub-group of patients with depression atbaseline.

FIG. 3: PANSS Negative Symptom Sub-Scale in sub-group of patients withdepression at baseline.

FIG. 4: Prosocial PANSS Factor Change from Baseline compared to Placebo.

DETAILED DESCRIPTION OF THE INVENTION

The current invention provides an unmet need in the treatment of notonly acute symptoms, but also residual symptoms of psychosis,particularly schizophrenia. Patients suffering from schizophrenia arecurrently treated with either conventional or atypical antipsychoticagents. These agents, which may be effective in treating positivesymptoms of psychosis, generally are inadequate for treating residualsymptoms. Thus, a different or additional treatment is needed to improveoutcomes. In one embodiment, the methods of the present invention use acompound of Formula I alone as hereinbefore described, or used in acombination of the compound of Formula I and one or more differentantipsychotic agents for the treatment of residual symptoms and acutesymptoms of psychosis.

As used herein “residual symptoms” include negative symptoms and generalpsychopathology symptoms as described in the Positive and NegativeSymptom Scale (PANSS) for Schizophrenia described in Kay et al.,Schizophr. Bull. (1987) 13(2):261-276, the contents of which areincorporated by reference in their entirety. Negative symptoms include:blunted affect, emotional withdrawal, poor rapport, passive/apatheticsocial withdrawal, difficulty in abstract thinking, lack of spontaneityand flow of conversation and stereotyped thinking. Generalpsychopathology symptoms include: somatic concern, anxiety, guiltfeelings, tension, mannerisms and posturing, depression, motorretardation, uncooperativeness, unusual thought content, disorientation,poor attention, lack of judgment and insight, disturbance of volition,poor impulse control, preoccupation and active social avoidance.Residual symptoms may also include depression, cognitive impairment andsleep disorders (e.g., insomnia). Of these residual symptoms, theCompounds of Formula I are particularly useful for the treatment ofpassive social withdrawal, stereotyped thinking, somatic concerns,anxiety, tension, active social avoidance and depression. Most patientswith schizophrenia exhibit deficits in social function preventingsuccessful reintegration into society. Social function deficits can bemeasured using the PANSS-Derived Prosocial factor. Prosocial factor iscomprised of items from the Positive, Negative and GeneralPsychopathology subscales such as active social avoidance, emotionalwithdrawal, passive social withdrawal, stereotyped thinking,hallucinatory behavior and suspiciousness. This factor is shown to besensitive to change in the clinical trial setting. Since the Compoundsof Formula I, particularly Compound A as defined in Example 1, reducenegative symptoms and also treat several other symptom domains, it isbelieved that the Compounds of Formula I may be useful in treatingsocial function deficits. Therefore, the compounds of the presentinvention are particularly useful in improving social integration andsocial function in patients suffering from schizophrenia. Socialfunction is the ability to recognize, understand, process and useexternal cues to solve problems, maintain work performance and conductinterpersonal relationships.

Treatment of these residual symptoms is also particularly effective inschizophrenic patients also suffering from depression. 60 mg of theCompound of Formula I, particularly Compound A as defined in Example 1in toluenesulfonic acid addition salt form, administered once daily inthe morning improves symptoms associated with schizophrenia measured bya statistically significant and clinically meaningful decrease in thePANSS total score after 28 days of treatment. This compound A also doesnot cause hyperprolactinemia, EPS/akathisia, weight gain orcardiovascular safety issues. At the same dosage, this compound A alsostatistically significantly improves the positive symptom subscale andthe general psychopathology subscale of the PANSS. Further, the Compoundof Formula I, particularly Compound A as defined in Example 1 intoluenesulfonic acid addition salt form at 60 mg improves negativesymptoms in a subgroup of patients with prominent negative symptoms atbaseline. Significantly, it also improves certain items on the negativesymptom and general psychopathology subscales consistent with improvedsocial function.

The term “acute symptoms” of psychosis or schizophrenia refers topositive symptoms of the PANSS such as delusions, conceptualdisorganization, hallucinatory behavior and suspiciousness.

The term “psychosis” refers to illnesses such as schizophrenia,delusional disorder, major depression with psychosis, bipolar disorderwith psychotic symptoms, brief psychotic disorder, schizophreniformdisorder, schizoaffective disorder or psychosis caused by a medicalcondition or substance use. Preferably, the patient suffering fromresidual symptoms of psychosis is a patient suffering from residualsymptoms of schizophrenia.

The term “bipolar disorder” refers to a disorder characterized byextreme shifts in mood. Individuals with bipolar disorder may experienceintense feelings of over-excitement, irritability, and impulsivity withgrandiose beliefs and racing thoughts, referred to as a manic episode.Symptoms of depression may include feeling tired, hopeless and sad, withdifficulty concentrating and thoughts of suicide. Some people experienceboth types of symptoms in the same “mixed” episode. Severe symptoms ofbipolar disorder can be associated with hallucinations or delusions,otherwise referred to as psychosis.

The words “treatment” and “treating” are to be understood accordingly asembracing prophylaxis and treatment or amelioration of symptoms ofdisease and/or treatment of the cause of the disease.

The term “patient” may include a human or non-human patient.

If not otherwise specified or clear from context, the following termsherein have the following meanings:

-   -   (i) “Alkyl” as used herein is a saturated or unsaturated        hydrocarbon moiety, e.g., one to twenty-one carbon atoms in        length, which may be linear or branched (e.g., n-butyl or        tert-butyl), preferably linear, unless otherwise specified. For        example, “C₁₋₂₁ alkyl” denotes alkyl having 1 to 21 carbon        atoms. In one embodiment, alkyl is optionally substituted with        one or more hydroxy or C₁₋₂₂alkoxy (e.g., ethoxy) groups. In        another embodiment, alkyl contains 1 to 21 carbon atoms,        preferably straight chain and optionally saturated or        unsaturated, for example R₁ is an alkyl chain containing 1 to 21        carbon atoms, preferably 6-15 carbon atoms, 16-21 carbon atoms,        e.g., so that together with the —C(O)— to which it attaches,        e.g., when cleaved from the compound of Formula I, forms the        residue of a natural or unnatural, saturated or unsaturated        fatty acid.        Methods of Making Compounds of Formula I

The compounds of the formula I and their pharmaceutically acceptablesalts may be made using the methods as described and exemplified in anyof the following patents or applications: U.S. Pat. Nos. 6,548,493;7,238,690; 6,552,017; 6,713,471; U.S. RE39680; U.S. RE39679;PCT/US08/03340; U.S. application Ser. No. 10/786,935; WO 2011/133224 A1,WO 2009/114181 and WO 2013/155505. If not commercially available,starting materials for these processes may be made by procedures, whichare selected from the chemical art using techniques which are similar oranalogous to the synthesis of known compounds. All references citedherein are hereby incorporated by reference in their entirety.

Compounds of Formula I refer to Compounds of Formula I or any of thecompounds described in Methods 1.1-1.50, which include:

in free or pharmaceutically acceptable salt form. The Compounds ofFormula I also include other specific compounds wherein Y is —C(H)(OH)—or —C(H)(OR₁) wherein R₁ is previously defined and X is —O—, —N(H)—, or—N(CH₃)—. These include, for example:

in free or pharmaceutically acceptable salt form. A specific Compound ofFormula I also includes Compound A which is the compound of Formula Iwherein X is —N(CH₃)— and Y is —C(O)—. The terms “Compounds of FormulaI” and “Compounds of Formula I” may be used interchangeably and may beused as a sole therapeutic agent, or they may also be used incombination or for co-administration with other active agents. Also, inthe methods of the present invention the phrase “a compound of FormulaI” may include more than one of the compounds of Formula I.

Compounds of Formula I may in some cases also exist in prodrug form. Aprodrug form is compound which converts in the body to an activeCompound of Formula I. The term “pro-drug” is an art recognized term andrefers to a drug precursor prior to administration that generates orreleases the active metabolite in vivo following administration, viasome chemical or physiological process. For example when the Compoundsof Formula I contain hydroxy or carboxy substituents, these substituentsmay form physiologically hydrolysable and acceptable esters. As usedherein, “physiologically hydrolysable and acceptable ester” means estersof Compounds of Formula I which are hydrolysable under physiologicalconditions to yield acids (in the case of Compounds of Formula I whichhave hydroxy substituents) or alcohols (in the case of Compounds ofFormula I which have carboxy substituents) which are themselvesphysiologically tolerable at doses to be administered. For example,wherein Y of the compound of Formula I is —C(H)(OR₁), and R₁ is aphysiologically hydrolysable and acceptable acyl for example—C(O)—C₁₋₂₁alkyl, e.g., —C(O)—C₃alkyl or —C(O)—C₉alkyl, these compoundsmay hydrolyze under physiological condition to yield a compound ofFormula I wherein Y is —C(H)(OH) on the one hand and C₁₋₂₁alkyl-C(O)OH,e.g., C₃alkyl-C(O)OH or C₉alkyl-C(O)OH on the other hand. In particular,Compounds of Formula I, wherein Y is —O—, —C(R₂)(OH)—, —C(R₃)(OR₁) or—C(O)—; R₁ is C₁₋₆ alkyl (e.g., methyl) and R₂ and R₃ are H or C₁₋₆alkyl (e.g., methyl) are active moieties. In contrast, Compounds ofFormula I, wherein R₁ is —C(O)—C₁₋₂₁alkyl is a physiologically labilemoiety, will have weak activity or no activity, but under physiologicalconditions will undergo hydrolysis to produce the Compounds of FormulaI, R₁ is cleaved off to leave —C(R₂)(OH) or —C(R₃)(OH) and the otherhydrolysis product is not toxic at relevant concentrations, e.g., atconcentrations which would be provided by in vivo hydrolysis of a dosageof the prodrug compound. Under some physiological conditions, Compoundsof Formula I, wherein R₁ is C₁₋₆ alkyl (e.g., methyl), may also under goin vivo conversion to the more active compound wherein R₁ is H, andtherefore these compounds may be considered to be both active moietiesand pro-drugs.

As will be appreciated the term prodrug thus embraces conventionalpharmaceutical prodrug forms. Wherein a prodrug (e.g., the compound offormula (I) wherein R₁ is —C(O)—C₁₋₂₁alkyl) is used, the dosage amountis calculated based on the amount of the active Compound of Formula I,e.g., Y is —O—, —C(R₂)(OH)—, —C(R₃)(OR₁) or —C(O)—; R₁ is C₁₋₆ alkyl(e.g., methyl), R₂ and R₃ are H or C₁₋₆ alkyl (e.g., methyl),particularly the compound of formula (I) wherein Y is C(═O) or Y isC(H)(OH) in free base form or in the salt form, e.g., in toluenesulfonicacid addition salt form.

The Compounds of Formula I may comprise one or more chiral carbon atoms.The compounds thus exist in individual isomeric, e.g., enantiomeric ordiastereomeric forms or as mixtures of individual forms, e.g.,racemic/diastereomeric mixtures. Any isomer may be present in which theasymmetric center is in the (R)-, (S)-, or (R,S)-configuration. Theinvention is to be understood as embracing both individual opticallyactive isomers as well as mixtures (e.g., racemic/diastereomericmixtures) thereof. Accordingly, the Compounds of Formula I may be aracemic mixture or they may be predominantly, e.g., in pure, orsubstantially pure, isomeric form, e.g., greater than 70%enantiomeric/diastereomeric excess (“ee”), preferably greater than 80%ee, more preferably greater than 90% ee, most preferably greater than95% ee. The purification of said isomers and the separation of saidisomeric mixtures may be accomplished by standard techniques known inthe art (e.g., column chromatography, preparative TLC, preparative HPLC,simulated moving bed and the like).

Geometric isomers by nature of substituents about a double bond or aring may be present in cis (Z) or trans (E) form, and both isomericforms are encompassed within the scope of this invention.

The Compounds of Formula I may be included as a sustained or delayedrelease formulation, e.g., depot formulation, e.g., by dispersing,dissolving or encapsulating the Compounds of Formula I in a polymericmatrix as described hereinbefore in P.1-P.7, such that the Compound iscontinually released as the polymer degrades over time. The release ofthe Compounds of Formula I from the polymeric matrix provides for thecontrolled- and/or delayed- and/or sustained-release of the Compounds,e.g., from the pharmaceutical depot composition, into a subject, forexample a warm-blooded animal such as man, to which the pharmaceuticaldepot is administered. Thus, the pharmaceutical depot delivers theCompounds of Formula I to the subject at concentrations effective fortreatment of the particular disease or medical condition over asustained period of time, e.g., 14-180 days, preferably about 30, about60 or about 90 days.

Polymers useful for the polymeric matrix in the Composition of theInvention (e.g., Depot composition of the Invention) may include apolyester of a hydroxy-fatty acid and derivatives thereof or otheragents such as polylactic acid, polyglycolic acid, polycitric acid,polymalic acid, poly-beta.-hydroxybutyric acid, epsilon.-capro-lactonering opening polymer, lactic acid-glycolic acid copolymer,2-hydroxybutyric acid-glycolic acid copolymer, polylacticacid-polyethylene glycol copolymer or polyglycolic acid-polyethyleneglycol copolymer), a polymer of an alkyl alpha-cyanoacrylate (forexample poly(butyl 2-cyanoacrylate)), a polyalkylene oxalate (forexample polytrimethylene oxalate or polytetramethylene oxalate), apolyortho ester, a polycarbonate (for example polyethylene carbonate orpolyethylenepropylene carbonate), a polyortho-carbonate, a polyaminoacid (for example poly-gamma.-L-alanine, poly-.gamma.-benzyl-L-glutamicacid or poly-y-methyl-L-glutamic acid), a hyaluronic acid ester, and thelike, and one or more of these polymers can be used.

If the polymers are copolymers, they may be any of random, block and/orgraft copolymers. When the above alpha-hydroxycarboxylic acids,hydroxydicarboxylic acids and hydroxytricarboxylic acids have opticalactivity in their molecules, any one of D-isomers, L-isomers and/orDL-isomers may be used. Among others, alpha-hydroxycarboxylic acidpolymer (preferably lactic acid-glycolic acid polymer), its ester,poly-alpha-cyanoacrylic acid esters, etc. may be used, and lacticacid-glycolic acid copolymer (also referred to aspoly(lactide-alpha-glycolide) or poly(lactic-co-glycolic acid), andhereinafter referred to as PLGA) are preferred. Thus, in one aspect thepolymer useful for the polymeric matrix is PLGA. As used herein, theterm PLGA includes polymers of lactic acid (also referred to aspolylactide, poly (lactic acid), or PLA). Most preferably, the polymeris the biodegradable poly(d,l-lactide-co-glycolide) polymer.

In a preferred embodiment, the polymeric matrix of the invention is abiocompatible and biodegradable polymeric material. The term“biocompatible” is defined as a polymeric material that is not toxic, isnot carcinogenic, and does not significantly induce inflammation in bodytissues. The matrix material should be biodegradable wherein thepolymeric material should degrade by bodily processes to productsreadily disposable by the body and should not accumulate in the body.The products of the biodegradation should also be biocompatible with thebody in that the polymeric matrix is biocompatible with the body.Particular useful examples of polymeric matrix materials includepoly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid,copolymers of the foregoing, poly(aliphatic carboxylic acids),copolyoxalates, polycaprolactone, polydioxonone, poly(ortho carbonates),poly(acetals), poly(lactic acid-caprolactone), polyorthoesters,poly(glycolic acid-caprolactone), polyanhydrides, and natural polymersincluding albumin, casein, and waxes, such as, glycerol mono- anddistearate, and the like. The preferred polymer for use in the practiceof this invention is dl-(polylactide-co-glycolide). It is preferred thatthe molar ratio of lactide to glycolide in such a copolymer be in therange of from about 75:25 to 50:50.

Useful PLGA polymers may have a weight-average molecular weight of fromabout 5,000 to 500,000 daltons, e.g., about 150,000 daltons, or 20,000to 200,000 daltons, for example, 24,000 to 38,000 daltons, or about113,000 daltons or about 159,000 daltons. For example, the PLGA polymerhas a weight-average molecular weight of 24,000 to 38,000 daltons.Dependent on the rate of degradation to be achieved, different molecularweight of polymers may be used. For a diffusional mechanism of drugrelease, the polymer should remain intact until all of the drug isreleased from the polymeric matrix and then degrade. The drug can alsobe released from the polymeric matrix as the polymeric excipientbioerodes.

The PLGA may be prepared by conventional methods, or may be commerciallyavailable. For example, PLGA can be produced by ring-openingpolymerization with a suitable catalyst from cyclic lactide, glycolide,etc. (see EP-0058481B2; Effects of polymerization variables on PLGAproperties: molecular weight, composition and chain structure).

It is believed that PLGA is biodegradable by means of the degradation ofthe entire solid polymer composition, due to the break-down ofhydrolysable and enzymatically cleavable ester linkages under biologicalconditions (for example in the presence of water and biological enzymesfound in tissues of warm-blooded animals such as humans) to form lacticacid and glycolic acid. Both lactic acid and glycolic acid arewater-soluble, non-toxic products of normal metabolism, which mayfurther biodegrade to form carbon dioxide and water. In other words,PLGA is believed to degrade by means of hydrolysis of its ester groupsin the presence of water, for example in the body of a warm-bloodedanimal such as man, to produce lactic acid and glycolic acid and createthe acidic microclimate. Lactic and glycolic acid are by-products ofvarious metabolic pathways in the body of a warm-blooded animal such asman under normal physiological conditions and therefore are welltolerated and produce minimal systemic toxicity.

In another embodiment, the polymeric matrix useful for the invention maycomprise a star polymer wherein the structure of the polyester isstar-shaped. These polyesters have a single polyol residue as a centralmoiety surrounded by acid residue chains. The polyol moiety may be, e.g., glucose or, e. g., mannitol. These esters are known and described inGB 2,145,422 and in U.S. Pat. No. 5,538,739, the contents of which areincorporated by reference.

The star polymers may be prepared using polyhydroxy compounds, e. g.,polyol, e. g., glucose or mannitol as the initiator. The polyol containsat least 3 hydroxy groups and has a molecular weight of up to about20,000 Daltons, with at least 1, preferably at least 2, e.g., as a mean3 of the hydroxy groups of the polyol being in the form of ester groups,which contain polylactide or co-polylactide chains. The branchedpolyesters, e. g., poly (d, l-lactide-co-glycolide) have a centralglucose moiety having rays of linear polylactide chains.

The sustained or delayed release formulation as hereinbefore describedmay comprise the polymer in the form of microparticles (e.g.,microspheres) or nanoparticles, or in a liquid form, with the Compoundsof Formula I dispersed or encapsulated therein. “Microparticles” ismeant solid particles that contain the Compounds of Formula I either insolution or in solid form wherein such compound is dispersed ordissolved within the polymer that serves as the matrix of the particle.By an appropriate selection of polymeric materials, a microparticleformulation can be made in which the resulting microparticles exhibitboth diffusional release and biodegradation release properties.

When the polymer is in the form of microparticles, the microparticlesmay be prepared using any appropriate method, such as by a solventevaporation or solvent extraction method. For example, in the solventevaporation method, the Compounds of Formula I and the polymer may bedissolved in a volatile organic solvent (for example a ketone such asacetone, a halogenated hydrocarbon such as chloroform or methylenechloride, a halogenated aromatic hydrocarbon, a cyclic ether such asdioxane, an ester such as ethyl acetate, a nitrile such as acetonitrile,or an alcohol such as ethanol) and dispersed in an aqueous phasecontaining a suitable emulsion stabilizer (for example polyvinylalcohol, PVA). The organic solvent is then evaporated to providemicroparticles with the Compounds of Formula I encapsulated therein. Inthe solvent extraction method, the Compounds of Formula I and polymermay be dissolved in a polar solvent (such as acetonitrile,dichloromethane, methanol, ethyl acetate or methyl formate) and thendispersed in an aqueous phase (such as a water/PVA solution). Anemulsion is produced to provide microparticles with the Compounds ofFormula I encapsulated therein. Spray drying is an alternativemanufacturing technique for preparing the microparticles.

Another method for preparing the microparticles of the invention is alsodescribed in both U.S. Pat. Nos. 4,389,330 and 4,530,840, the contentsof which are incorporated by reference.

The microparticle of the present invention can be prepared by any methodcapable of producing microparticles in a size range acceptable for usein an injectable composition. One preferred method of preparation isthat described in U.S. Pat. No. 4,389,330. In this method the activeagent is dissolved or dispersed in an appropriate solvent. To theagent-containing medium is added the polymeric matrix material in anamount relative to the active ingredient that provides a product havingthe desired loading of active agent. Optionally, all of the ingredientsof the microparticle product can be blended in the solvent mediumtogether.

Solvents for the Compounds of Formula I and the polymeric matrixmaterial that can be employed in the practice of the present inventioninclude organic solvents, such as acetone; halogenated hydrocarbons,such as chloroform, methylene chloride, and the like; aromatichydrocarbon compounds; halogenated aromatic hydrocarbon compounds;cyclic ethers; alcohols, such as, benzyl alcohol; ethyl acetate; and thelike. In one embodiment, the solvent for use in the practice of thepresent invention may be a mixture of benzyl alcohol and ethyl acetate.Further information for the preparation of microparticles useful for theinvention can be found in U.S. Patent Publication Number 2008/0069885,the contents of which are incorporated herein by reference in theirentirety.

The amount of the Compounds of Formula I incorporated in themicroparticles usually ranges from about 1 wt % to about 90 wt. %,preferably 30 to 50 wt. %, more preferably 35 to 40 wt. %. By weight %is meant parts of the Compounds of Formula I per total weight ofmicroparticle.

The sustained or delayed release formulation may comprise apharmaceutically-acceptable diluent or carrier, such as a water misciblediluent or carrier.

In one embodiment, the sustained or delayed release formulation is along-acting injectable formulation. In a further embodiment, thelong-acting injectable is formulated using polymeric microspheres, e.g.,microspheres comprising a PLGA matrix with Compounds of Formula I infree or pharmaceutically acceptable salt form dispersed, dissolved orencapsulated therein. In a preferred embodiment, the PLGA polymer isabout 75:25 PLA/PLG (lactide:glycolide) with either carboxylic acid orcarboxylic ester end groups. In a preferred embodiment, the Compound ofFormula I is present in the microsphere as its free base. Themicrospheres may be prepared using methods known in the art, forexample, by an emulsification-solvent evaporation method withoutmicro-sieving, or an emulsification-solvent evaporation method with drymicro-sieving, or an emulsification-solvent evaporation method with wetmicro-sieving.

The rate at which the PLGA microspheres degrades depends largely on thechosen molecular weight range of the polymer molecules and on the sizeof the microspheres. In one embodiment, the average molecular weightrange for the PLGA polymer is 24,000 to 38,000 daltons. In anotherembodiment, the PLGA polymer has an average molecular weight of about113,000 daltons. In still another embodiment, the PLGA polymer has anaverage molecular weight of about 159,000 daltons. In some embodiments,the time frame for complete degradation of the microspheres and releaseof the encapsulated drug compounds is, e.g., less than 6 months, lessthan 4 months, less than 3 months, less than 2 months, or less than 1month.

The diameter of the microspheres, e.g., the average diameter (or D₅₀),the 10^(th) percentile diameter (D₁₀), the 25^(th) percentile diameter(D₂₅), the 75^(th) percentile diameter (D₇₅), or the 90^(th) percentilediameter (D₉₀), can be from about 1 μm to about 100 μm, or about 2 μm toabout 80 μm, or from about 2 μm to about 60 μm, or about 2 μm to about50 μm, or about 2 μm to about 40 μm, or about 2 μm to about 30 μm, orabout 5 μm to about 35 μm, or from about 5 μm to about 25 μm, or fromabout 5 μm to about 20 μm, or from about 10 μm to about 20 μm, or about10 μm to about 200 μm, from about 20 μm to about 160 μm, or from about20 μm to about 120 μm, or from about 20 μm to about 100 μm, or fromabout 20 μm to about 80 μm, or from about 20 μm to about 70 μm, or fromabout 20 μm to about 60 μm, or from about 20 μm to about 50 μm, or fromabout 20 m to about 40 μm, or from about 20 μm to about 30 μm, or fromabout 25 μm to about 70 μm, or from about 25 μm to about 60 μm, or fromabout 25 μm to about 50 μm, or from about 25 μm to about 40 μm, or fromabout 30 μm to about 60 μm, or from about 30 to 50 μm, or from about 30μm to about 40 μm, or from about 30 μm to about 120 μm, or from about 40μm to about 120 μm, or from about 40 μm to about 100 μm, or from about40 μm to about 80 μm, or from about 40 μm to about 70 μm, or from about40 μm to about 60 μm, or from about 40 μm to about 50 μm, or from about50 μm to about 100 μm, or from about 50 μm to about 80 μm, or from about50 μm to about 70 μm, or from about 50 μm to about 60 μm, or from about60 μm to about 100 μm, or from about 60 μm to about 90 μm, or from about60 μm to about 80 μm, or from about 60 μm to about 70 μm, or from about70 μm to about 100 μm, or from about 70 μm to about 90 μm, or from about70 μm to about 80 μm, or from about 75 μm to about 110 μm, or from about40 μm to about 160 μm, or from about 50 μm to about 160 μm, or fromabout 50 μm to about 120 μm, or about 20 μm, about 30 μm, about 40 μm,about 50 μm, about 60 μm, about 70 μm, about 80 μm, about 90 μm, orabout 100 μm. Such particle size measurements can be made, for example,using photomicroscopy, scanning electron microscopy, laser diffraction,light scattering, and other techniques known to those skilled in theart.

The amount of drug encapsulated in each microsphere, on average, can befrom about 5% by weight to about 50% by weight, for example, 10% byweight to about 50% by weight, or from about 20% by weight to about 40%by weight, or from about 30% by weight to about 35% by weight, or about8.5% by weight, or about 16% by weight, or about 30% by weight, or about35% by weight, or about 40% by weight. In a preferred embodiment, theamount of drug encapsulated in each microsphere is about 8.5% by weightor about 16% by weight.

Details of Osmotic-controlled Release Oral delivery System compositionmay be found in EP 1 539 115 (U.S. Pub. No. 2009/0202631) and WO2000/35419, the contents of each of which are incorporated by referencein their entirety.

A “therapeutically effective amount” is any amount of the Compounds ofFormula I which, when administered to a subject suffering from a diseaseor disorder, is effective to cause a reduction, remission, or regressionof the disease or disorder over the period of time as intended for thetreatment.

Depression is estimated to occur in 50% of schizophrenic patients.Schizophrenia patients with co-morbid depression, when compared topatients with only schizophrenia, generally have worse overall mentaland physical health, lower quality of life, greater impairment of socialrelationships, less satisfaction with sleep, ability to perform dailyactivities, capacity for work, transportation, social support andself-esteem. Therefore, depressive symptoms exacerbate deficits inpsychosocial functioning and heighten risk for psychotic relapse. Unlikedopamine receptor antagonists, Compounds of Formula I, particularlyFormula A as defined in Example 1 normalize brain dopamine activity,particularly in the prefrontal cortex. The Compounds of Formula I,particularly Formula A as defined in Example 1, bind to 5-HT_(2A) anddopamine D₂ receptors. In addition, the compounds of Formula I alsomodulate glutamatergic phosphoprotein (D₁/GluN_(2B)) and dopaminephosphoprotein (DPPM). Compounds of Formula I also exhibit nanomolarbinding affinity for the serotonin transporter compared to knownantidepressants. Therefore, in addition to treating acute symptoms(e.g., hallucinations and delusions) and residual symptoms, thecompounds of Formula I are also useful for the treatment of depressionand/or sleep disorders. For schizophrenic patients who also suffer fromdepression, the Compounds of Formula I are particularly useful forimproving total PANSS and negative symptoms. While one of the atypicalantipsychotic drugs, risperidone, is also useful for treating somenegative symptoms, this compound is less effective compared to thesub-group of patients with depression at the baseline treated with theCompound of Formula I (See FIGS. 2 and 3 and Example 1). Therefore, incertain embodiments, the methods of the current invention areparticularly useful for the treatment of depression and/or sleepdisorders in patients suffering from acute and/or residual symptoms ofpsychosis as well as for the treatment of acute and/or residual symptomsof psychosis in patients suffering from depression and/or sleepdisorders.

In a further embodiment, the invention provides a method of treatingresidual symptoms by administering the compound of Formula I incombination with one or more other therapeutic agents such asantipsychotic agent(s) and/or anti-depressive agent(s) and/or hypnoticagents. In such methods, the antipsychotic and/or anti-depressive and/orhypnotic agents may be an adjunct to the compound of Formula I or thecompound of Formula I may be an a to the antipsychotic agent and/oranti-depressive agent and/or hypnotic agent. As used herein the term“adjunctive” or “adjunct” refers to any treatment that is used inconjunction with another to increase the chance of cure, or to increasethe first treatment's efficacy. In other words, adjunctive therapy actsas an aid to the primary treatment. In another embodiment, the compoundof formula I is used as a mono-therapy to treat acute symptoms and/orresidual symptoms of schizophrenia as well as depression and/or sleepdisorders (e.g., insomnia) in patients suffering from schizophrenia.

Other therapeutic agents which can be optionally administered to apatient in need thereof include compounds that modulate GABA activity(e.g., enhances the activity and facilitates GABA transmission), aGABA-B receptor agonist, a 5-HT modulator (e.g., a 5-HT_(1A) receptoragonist, a 5-HT_(2A) receptor antagonist, a 5-HT_(2A) receptor inverseagonist, etc.), a melatonin receptor agonist, an ion channel modulator(e.g., blocker), a serotonin-2 receptor antagonist/reuptake inhibitor(SARIs), an orexin receptor antagonist, an H3 receptor agonist, anoradrenergic receptor antagonist, a galanin receptor agonist, a CRHreceptor antagonist, human growth hormone, a growth hormone receptoragonist, estrogen, an estrogen receptor agonist, a neurokinin-1 drug,and antipsychotic agents, e.g., atypical antipsychotic agents, in freeor pharmaceutically acceptable salt form.

The term “GABA” refers to gamma-aminobutyric acid. The GABA compoundsare compounds which bind to the GABA receptor, and include, but are notlimited to one or more of doxepin, alprazolam, bromazepam, clobazam,clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam,midazolam, nitrazepam, oxazepam, temazapam, triazolam, indiplon,zopiclone, eszopiclone, zaleplon, Zolpidem, gabaxadol, vigabatrin,tiagabine, EVT 201 (Evotec Pharmaceuticals) or estazolam.

Other optional therapeutic agents are 5HT_(2A) receptor antagonists suchas ketanserin, risperidone, eplivanserin, volinanserin (Sanofi-Aventis,France), pruvanserin, pimavanserin (ACP-103), MDL 100907(Sanofi-Aventis, France), HY10275 (Eli Lilly), APD125 (ArenaPharmaceuticals, San Diego, Calif.), or AVE8488 (Sanofi-Aventis,France).

Still other optional therapeutic agents include pizotifen.

Other optional therapeutic agents are 5HT_(1A) receptor agonists such asrepinotan, sarizotan, eptapirone, buspirone or MN-305 (MediciNova, SanDiego, Calif.).

Other optional compounds are melatonin receptor agonists such asmelatonin, ramelteon (ROZEREM®, Takeda Pharmaceuticals, Japan), VEC-162(Vanda Pharmaceuticals, Rockville, Md.), PD-6735 (Phase II Discovery oragomelatine.

Other optional therapeutic agents are ion channel blockers such aslamotrigine, gabapentin or pregabalin.

Other optional therapeutic agents are orexin receptor antagonists suchas orexin, a 1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), GW649868(GlaxoSmithKline) or a benzamide derivative, for example.

Other optional therapeutic agents are serotonin-2 receptorantagonist/reuptake inhibitors (SARI) such as Org 50081(Organon-Netherlands), ritanserin, nefazodone, serzone or trazodone.

Other optional therapeutic agents are neurokinin-1 drugs such asCasopitant (GlaxoSmithKline).

Specific examples of additional therapeutic agents include modafinil,armodafinil, doxepin, alprazolam, bromazepam, clobazam, clonazepam,clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam,nitrazepam, oxazepam, temazapam, triazolam, indiplon, zopiclone,eszopiclone, zaleplon, zolpidem, gabaxadol, vigabatrin, tiagabine, EVT201 (Evotec Pharmaceuticals), estazolam, ketanserin, risperidone,eplivanserin, volinanserin (Sanofi-Aventis, France), pruvanserin, MDL100907 (Sanofi-Aventis, France), HY10275 (Eli Lilly), APD125 (ArenaPharmaceuticals, San Diego, Calif.), AVE8488 (Sanofi-Aventis, France),repinotan, sarizotan, eptapirone, buspirone, MN-305 (MediciNova, SanDiego, Calif.), melatonin, ramelteon (ROZEREM®, Takeda Pharmaceuticals,Japan), VEC-162 (Vanda Pharmaceuticals, Rockville, Md.), PD-6735 (PhaseII Discovery), agomelatine, lamotrigine, gabapentin, pregabalin, orexin,a 1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), GW649868(GlaxoSmithKline), a benzamide derivative, Org 50081(Organon-Netherlands), ritanserin, nefazodone, serzone, trazodone,Casopitant (GlaxoSmithKline), amitriptyline, amoxapine, bupropion,citalopram, clomipramine, desipramine, doxepin, duloxetine,escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid,maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine,phenlzine sulfate, protriptyline, sertraline, tranylcypromine,trazodone, trimipramine, velafaxine, chlorpromazine, haloperidol,droperidol, fluphenazine, loxapine, mesoridazine molindone,perphenazine, pimozide, prochlorperazine promazine, thioridazine,thiothixene, trifluoperazine, clozapine, aripiprazole, olanzapine,quetiapine, risperidone, ziprasidone, paliperidone, asenapine,lurasidone, iloperidone, cariprazine, amisulpride, zotepine, sertindole,in free or pharmaceutically acceptable salt form.

The combination compositions of the invention can include mixtures ofthe combined drugs, as well as two or more separate compositions of thedrugs, which individual compositions can be, for example,co-administered together to a patient at the same of different times.

In another aspect, the invention provides use of the Compound of FormulaI or any of the pharmaceutical compositions described hereinbefore(Compositions P.1-P.7 and Compositions 2, and 2.1-2.17) comprising theCompound of Formula I in free or pharmaceutically acceptable salt formas described in Methods A or 1.1-1.50, wherein the compound is inadmixture with an antioxidant. In a preferred embodiment, long actinginjectable microsphere formulations of the present invention contain anantioxidant. In some embodiments, the antioxidant is a water solubleantioxidant (e.g., ascorbic acid, lipoic acid), while in otherembodiments, the antioxidant is a lipid-soluble antioxidant (e.g.,lipoic acid, vitamin E, tocopherols, carotenes, and phenolicantioxidants). In some embodiments, the antioxidant is a neutral orweakly basic antioxidant. Other possible antioxidants include catalyticantioxidants (e.g., ebselen) and metal-containing antioxidants. In apreferred embodiment, the antioxidant is a phenolic antioxidant, such asbutylated hydroxytoluene (BHT) or butylated hydroxyanisole (BHA). In amore preferred embodiment, the antioxidant is BHT.

Dosages employed in practicing the present invention will of course varydepending, for example, on the particular disease or condition to betreated, the particular Compound of Formula I used, the mode ofadministration, and the therapy desired. Unless otherwise indicated, anamount of the Compound of Formula I for administration (whetheradministered as a free base, prodrug or as a salt form) refers to or isbased on the amount of the Compound of Formula I in free base form(i.e., the calculation of the amount is based on the free base amount).In a particular embodiment, however, the dosage of the Compound ofFormula I is administered based on the amount of the salt form, e.g.,the toluenesulfonic acid addition salt form. Compounds of Formula I maybe administered by any suitable route, including orally, parenterally ortransdermally, but are preferably administered orally. As a monotherapy,the compound of Formula I may be administered at about 1 mg to 120 mgper day or 10 mg to 120 mg per day, or 10 mg to 60 mg per day, or 10 mgto 40 mg per day, or 1 mg to 10 mg per day, or 10 mg per day, 20 mg perday, 40 mg per day or 60 mg per day, preferably about 60 mg of thecompound in toluenesulfonic acid addition salt form per day. Wherein 120mg is administered, it is preferably administered at night time.

As a long-acting injectable microsphere formulation, the dosage of theCompound of Formula I depends on both the average loading of drug withinthe microspheres (expressed as % w/w) and on the dosage of microspheresadministered (mg/kg). As a monotherapy, the Compound of Formula I may beadministered as microspheres to provide a dosage of 1 to 50 mg/kg of theCompound of Formula I, for example, 5 to 25 mg/kg, preferably 5-10mg/kg, for example about 5 mg/kg. A dose of about 5 mg/kg of thecompound of Formula I can be provided, for example, by employing a doseof 60 mg/kg of microspheres, wherein each microsphere contains onaverage a loading of about 8.5% w/w of the Compound of Formula I.

The dosages of a compound of Formula I and/or the other anti-psychoticand/or anti-depressive agent of Method A can be the same as or lowerthan the approved dosage for the drug, the clinical or literature testdosage or the dosage used for the drug as a monotherapy. For example thedaily dosage of compound of Formula I to be administered in combinationwith another anti-psychotic agent and/or an anti-depressive agent isabout 1 mg to about 140 mg, in another embodiment about 1 mg to about120 mg, in another embodiment about 10 mg to about 120 mg, in anotherembodiment about 10 mg to about 60 mg, in another embodiment about 10 mgto about 40 mg, in another embodiment about 20 mg to about 40 mg, inanother embodiment about 1 mg to about 10 mg, and in still anotherembodiment, about 60 mg of the compound in free base or toluenesulfonicacid addition salt form. The amount of antipsychotic agent to beadministered in combination with the compound of Formula I is about 0.01mg to about 1000 mg, in another embodiment, about 0.1 mg to about 600mg, e.g., about 1 mg to about 200 mg, e.g., about 1 mg to about 50 mg,e.g., about 1 mg to about 15 mg, e.g., about 4 mg. The amount ofanti-depressive agent to be administered in combination with thecompound of Formula I is about 0.01 mg to about 2000 mg, in anotherembodiment about 0.1 mg to about 200 mg, in another embodiment about 10mg to about 200 mg. In a particular embodiment, the second therapeuticagent is the antipsychotic agent risperidone at a daily dose of about 2mg to about 4 mg and the antidepressant is sertraline and the dailydosage of sertraline is between about 20 mg and 100 mg.

In a specific embodiment, the dosages of a compound of Formula I and/orthe second (or third) therapeutic agents of Method A are lower than whenused in a monotherapy. Therefore, in a particular embodiment, the dailydosage of a compound of Formula I is lower than 100 mg once daily, orless than 60 mg, or less than 40 mg, or less than 30 mg, or less than 20mg, or less than 10 mg. In another preferred embodiment, the dosages ofboth the Compound of Formula I and the anti-psychotic agent and/or theanti-depressive agent of Method A are lower than the dosages used forthe individual drugs as monotherapy. Therefore, in a particularembodiment, for example, Method A comprises administering (1) a Compoundof Formula I at a dosage lower than 100 mg once daily, e.g., less than60 mg or less than 40 mg; and/or (2) an antidepressant, for example anSSRI such as sertraline, at a daily dosage of less than 50 mg, morepreferably, less than 20 mg, still more preferably, less than 10 mg,most preferably less than 6 mg; and/or (3) an antipsychotic agent, forexample risperidone, at a daily dosage of less than 4 mg, in free orpharmaceutically acceptable salt form.

For the treatment of the disorders disclosed herein wherein thesustained or delayed release formulation is used to achieve longerduration of action, the dosages will be higher relative to the shorteraction composition, e.g., higher than 1-100 mg, e.g., 25 mg, 50 mg, 100mg, 500 mg, 1,000 mg, or greater than 1000 mg. In a particularembodiment, the dosage regimen for sustained or delayed releaseformulation includes an initial oral immediate release dosage along withdepot release so as to provide a steady-state blood level of the drug.Duration of action of the Compounds of Formula I may be controlled bymanipulation of the polymer composition, i.e., the polymer:drug ratioand microparticle size. Wherein the formulation of the invention is adepot formulation, administration by injection is preferred. In apreferred embodiment, the formulation is a long-acting injectablemicrosphere formulation, as described hereinabove.

The compounds to be administered in the methods of the present inventioncan be in the form of free acid or free base or as pharmaceuticallyacceptable salts. The phrase “pharmaceutically acceptable salts” refersto derivatives of the above disclosed compounds wherein the parentcompound is modified by making acid or base salts thereof. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid salts of basic residues such as amines; alkalior organic salts of acidic residues such as carboxylic acids; and thelike. The pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycolic, stearic, lactic,malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, and the like. Preferably, the Compoundsof Formula I are in a toluenesulfonic acid addition salt form.

The pharmaceutically acceptable salts of the compounds to be used in themethods of the invention can be synthesized from the parent compoundwhich contains a basic or acidic moiety by conventional chemicalmethods. Generally, such salts can be prepared by reacting the free baseforms of these compounds with a stoichiometric amount of the appropriateacid in water or in an organic solvent, or in a mixture of the two;generally, non-aqueous media such as diethyl ether, ethyl acetate,ethanol, isopropanol, or acetonitrile are preferred. Further details forthe preparation of these salts, e.g., toluenesulfonic acid salts inamorphous or crystal form, may be found in PCT/US08/03340 (WO2008/112280) and/or WO 2009/114181 and WO 2011/133224.

Pharmaceutical compositions comprising the Compounds of Formula I may beprepared using conventional diluents or excipients and techniques knownin the galenic art. For example the compounds can be administered in awide variety of different dosage forms, i.e., they may be combined withvarious pharmaceutically-acceptable inert carriers in the form oftablets, capsules, lozenges, troches, hard candies, powders, sprays,aqueous suspension, injectable solutions, elixirs, syrups, and the like.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium phosphate); lubricants (e.g. magnesium stearate, talc orsilica); disintegrants (e.g. potato starch or sodium starch glycolate);or wetting agents (e.g. sodium lauryl sulfate). The tablets may becoated by methods well known in the art. Liquid preparations for oraladministration may take the form of, for example, solutions, syrups orsuspensions, or they may be presented as a dry product for constitutionwith water or other suitable vehicle before use. Such liquidpreparations may be prepared by conventional means with pharmaceuticallyacceptable additives such as suspending agents (e.g. sorbitol syrup,methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g.lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily estersor ethyl alcohol); and preservatives (e.g. methyl or propylp-hydroxybenzoates or sorbic acid).

For immediate release formulation, the compound of Formula I, in free orpharmaceutically acceptable salt form as hereinbefore described may beformulated with a pharmaceutically acceptable diluents or carrier. Forsustained or delayed release formulation, the compound of the compoundof Formula I, in free or pharmaceutically acceptable salt form ashereinbefore described may be formulated as hereinbefore described inany of Compositions P.1-P.7.

In a particular embodiment, the Compound of Formula I is formulated in acapsule as follows:

Composition % w/w Placebo 60 mg Compound of Formula I wherein X is 20 0—N(CH₃)— and Y is —C(O)— in toluene sulfonic acid addition salt form;Mannitol (Perlitol ® 100SD NF) 73.7 73.7 Croscarmellose Na 5 5 GlycerylMonostearate 1 1 Imperial Talc 500 0.3 0.3

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The Compounds of Formula I may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g. in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The Compounds of Formula I may also be formulated in rectal compositionssuch as suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theCompounds of Formula I are conveniently delivered in the form of asolution or suspension from a pump spray container that is squeezed orpumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of an active compound and a suitable powder base such as lactose orstarch. When aqueous suspensions and/or elixirs are desired for oraladministration, the essential active ingredient(s) therein may becombined with various sweetening, or flavoring agents, coloring matteror dyes and, if so desired, emulsifying and/or suspending agents aswell, together with such diluents as water, ethanol, propylene glycol,glycerin and various like combinations thereof.

All of the references cited hereinbefore are hereby incorporated inreference in their entirety.

The following example is to illustrate the invention but should not beinterpreted as a limitation thereon.

Example 1 Treatment of Acute as Well as Residual Symptoms ofSchizophrenia

For purposes of this example, Compound A refers to the compound ofFormula I wherein X is —N(CH₃)— and Y is —C(O)—; tosylate salt unlessotherwise indicated. A randomized, double-blind, placebo-controlled,in-patient trial is performed. Four treatment arms, 4-week treatmentduration, QAM dosing are performed as follows: 60 mg of Compound A; 120mg of Compound A; positive control (4 mg Risperidone); and placebo. Theprimary outcome is measured by the change from baseline on Positive andNegative Syndrome Scale (PANSS) Total Score at Day 28. Secondarymeasures explore key differentiating features.

60 mg Compound A Treatment Arm receives 60 mg of Compound A once dailyfor 28 days. 120 mg Compound A Treatment Arm receives 60 mg Compound Aon Study Day 1 followed by 120 mg Compound A once daily for 27 days.Risperidone Treatment Arm receives 2 mg risperidone on Study Day 1followed by 4 mg risperidone once daily for 27 days. Placebo TreatmentArm receives placebo once daily for 28 days. All doses are administeredin the morning with breakfast.

Key inclusion criteria: Clinical diagnosis of schizophrenia according toDSM-IV-TR is confirmed by modified SCID-CT. Screening Brief PsychiatricReading Scale (BPRS) score of 40 or greater (18-items scored 1-7 each).Minimum score of 4 or higher on at least two of the following positiveitems: suspiciousness, conceptual disorganization, hallucinatorybehavior, unusual thought content. Current exacerbated episode lasts nolonger than 4 weeks. Sufficient history and/or independent reporter mustverify that current state is an exacerbated state for the individual.Prior response to antipsychotic therapy within the last 5 years, definedas clinically significant and documented decrease in delusions and/orhallucinations during a documented exacerbated episode (and at least 3months prior exposure to antipsychotic therapy).

The trial has a high subject completion rate (74%) compared to anaverage of 62% completion rate in other 4-week antipsychotic trials. 19%discontinues during the study treatment period (during Day 1-28). 7%completes study treatment through Day 28, but are lost to follow up. At60 mg, the trial shows that Compound A demonstrates antipsychoticefficacy on primary endpoint total PANSS change from baseline at Day 28:

TABLE 1 LS Mean Change from Baseline on Day 28 LS Mean Total PANSSDifference Treatment Arm (±SE) using from Effect (N/arm) MMRM/ITTPlacebo p-value Size Placebo (N = 80)  −7.4 ± 1.7 n/a n/a n/a 60 mgCompound A −13.2 ± 1.7 −5.8 0.017 0.4 (N = 76) 120 mg Compound A  −8.3 ±1.7 −0.9 0.708 0.1 (N = 80) 4 mg Risperidone −13.4 ± 1.7 −6.0 0.013 0.4(N = 75)

For patients with prominent negative symptoms at baseline (e.g.,patients with a score of 4 or higher on at least 3 negative symptomitems at baseline), 60 mg of Compound A improves negative symptomsqualitatively (see FIG. 1).

In a subgroup of patients with symptoms of depression that are secondaryto schizophrenia measured by the cut-off score for depression (CalgaryDepression Scale for Schizophrenia, CDSS, score >6) at baseline (whichaccounts for approximately 16% of the patients in the study), 60 mg ofCompound A significantly reduces depression as measured by the CDSS(p=0.044). Compound A at 60 mg also robustly improves total PANSS (SeeFIG. 2) and negative symptoms (See FIG. 3).

At 60 mg, Compound A is also shown to significantly improve theProsocial PANSS Factor change from baseline compared to placebo (SeeFIG. 4).

Examples 2-10 Preparation of Long-Acting Injectable MicrosphereFormulations Example 2 Preparation of the PLGA (PLA/PLG=75/25, 0.32-0.44dl/g) Microspheres of Compound a Free Base (Lot A)

For purposes of Examples 2-10, Compound A refers to the compound ofFormula I wherein X is —N(CH₃)— and Y is —C(O)— in free base form.

2 g of Poly(vinyl alcohol) (PVA, 87-89% hydrolyzed, typical molecularweight 13,000-23,000) in 400 mL of deionized water is sonicated in abath sonicator for 5-10 min and then filtered to give 0.5% PVA aqueoussolution. The filtrate is transferred to a 500 mL flat bottom flask.0.80 g of Compound A and 1.2 g of PLGA polymer (PLA/PLG=75/25, 0.32-0.44dl/g, acid end groups) are dissolved in 15 mL of dichloromethane. Thissolution is added into the 0.5% PVA aqueous solution dropwise withvigorous stirring. A mechanical overhead stirrer is used and thestirring speed is around 700 ppm during the addition. After thecompletion of the addition, the mixture is stirred at this speed for anhour and then stirred at approximately 550 ppm for 4 hours. An argonstream is applied throughout the process to promote the evaporation ofdichloromethane from the aqueous solution. A size 75 μm microsieve isstacked on the top of a 20 μm microsieve. The suspension is slowlypoured onto the stacked microsieves and then washed with water at leastfive times. The microspheres collected on the 20 μm microsieve istransferred into a 50 mL falcon tube with deionized water and thenlyophilized to give 1.43 g of Compound A PLGA microspheres with a sizedistribution of 20-60 μm. The drug content in the obtained microspheresis 37.5%, as determined by HPLC. The initial loading for thispreparation is 40% (calculated based upon 0.8 g of Compound A free basein 1.2 g of the PLGA polymer). Drug entrapment efficiency is 93.8%.

Example 3 Preparation of the PLGA (PLA/PLG=75/25, 0.32-0.44 dl/g)Microspheres of Compound a Free Base (Lot B)

This lot of Compound A PLGA microspheres is prepared using a proceduresimilar to the one described in Example 2 except that sterilized wateris used in the whole process instead of deionized water and all labwaresin touch with microspheres are sterilized. 1.49 g of Compound A PLGAmicrospheres with a size distribution of 20-50 μm are obtained. The drugcontent in the obtained microspheres is 38%, as determined by HPLC. Theinitial drug loading for this lot is 40% and drug entrapment efficiencyis 85.8%.

Example 4 Preparation of the PLGA (PLA/PLG=75/25, 0.89 dl/g)Microspheres of Compound a Free Base (Lot C)

2 g of Poly(vinyl alcohol) (PVA, 87-89% hydrolyzed, typical molecularweight 13000-23000) in 400 mL of sterilized water is sonicated in a bathsonicator for 5-10 min and then filtered to give 0.5% PVA aqueoussolution. The filtrate is transferred to a 500 mL flat bottom flask.0.80 g of Compound A and 1.2 g of PLGA polymer (PLA/PLG=75/25; 0.89dl/g; MW: 159,000 d; ester end groups) are dissolved in 16 mL ofdichloromethane with sonication. This solution is added into the 0.5%PVA aqueous solution dropwise with vigorous stirring. A mechanicaloverhead stirrer is used and the stirring speed is ˜700 ppm during theaddition. After the completion of the addition, the mixture is stirredat this speed for an hour and then stirred at approximately 550 ppm for4 hours. An argon stream is applied throughout the process to promotethe evaporation of dichloromethane from the aqueous solution. A size 75μm microsieve is stacked on the top of a 20 μm microsieve. Thesuspension is slowly poured onto the stacked microsieves and then washedwith water at least five times. The microspheres collected on the 20 μmmicrosieve is transferred into a 50 mL falcon tube with deionized waterand then lyophilized to give 0.78 g of Compound A PLGA microspheres witha size distribution of 20-70 μm. The drug content in the obtainedmicrospheres is 36%, as determined by HPLC. The initial loading for thispreparation is 40% (calculated based upon 0.8 g of Compound A free basein 1.2 g of the PLGA polymer). Drug entrapment efficiency is 90%.

Example 5 Preparation of the PLGA (PLA/PLG=75/25, 0.68 dl/g)Microspheres of Compound a Free Base (Lot D)

This lot of Compound A PLGA microspheres is prepared using a proceduresimilar to the one described in Example 4 except that a new type of PLGApolymer (PLA/PLG=75/25; 0.68 dl/g; MW: 113,000 d; acid end groups) isused in the microsphere preparation. 1.11 g of Compound A PLGAmicrospheres with a size distribution of 25-75 μm are obtained. The drugcontent in the obtained microspheres is 36%, as determined by HPLC. Theinitial drug loading for this lot is 40% and drug entrapment efficiencyis 90%.

Example 6 Preparation of the PLGA (PLA/PLG=75/25, 0.68 dl/g)Microspheres of Compound a Free Base (Lot E)

This lot of PLGA microspheres is prepared using a procedure similar tothe one described in Example 4 except that a different type of PLGApolymer (PLA/PLG=75/25; 0.68 dl/g; MW: 113,000 d; acid end groups) and amicrosieve with a pore size of 75 μm is used in the microspherepreparation. 0.25 g of Compound A PLGA microspheres with a sizedistribution of 75-110 μm are obtained. The drug content in the obtainedmicrospheres is 37%, as determined by HPLC. The initial drug loading forthis lot is 40% and drug entrapment efficiency is 93%.

Example 7 Preparation of the PLGA (PLA/PLG=75/25, 0.68 dl/g)Microspheres of Compound a Free Base (Lot F)

This lot of Compound A PLGA microspheres is prepared using a proceduresimilar to the one described in Example 4 except that a new type of PLGApolymer (PLA/PLG=75/25; 0.68 dl/g; MW: 113,000 d; acid end groups) andmicrosieves with pore sizes of 53 μm and 106 μm, respectively, are usedin the microsphere preparation. 1.22 g of PLGA microspheres with a sizedistribution of 52-101 μm are obtained. The drug content in the obtainedmicrospheres is 37%, as determined by HPLC. The initial drug loading forthis lot is 40% and drug entrapment efficiency is 93%.

Example 7-A Preparation of the PLGA (PLA/PLG=75/25, 0.32-0.44 dl/g)Microspheres of Compound a Free Base (Lot F)

2 g of Poly(vinyl alcohol) (PVA, 87-89% hydrolyzed, typical molecularweight 13000-23000) in 400 mL of sterilized water is sonicated in a bathsonicator for 5-10 min and then filtered to give 0.5% PVA aqueoussolution. The filtrate is transferred to a 500 mL flat bottom flask.0.40 g of Compound A and 2.1 g of PLGA polymer (PLA/PLG=75/25; 0.32-0.44dl/g; acid end groups) are dissolved in 21 mL of dichloromethane withsonication. This solution is added into the 0.5% PVA aqueous solutiondropwise with vigorous stirring. A mechanical overhead stirrer is usedand the stirring speed is ˜500 ppm during the addition. After thecompletion of the addition, the mixture is stirred at approximately 500ppm for 5 hours. An argon stream is applied throughout the process topromote the evaporation of dichloromethane from the aqueous solution. Asize 75 μm microsieve is stacked on the top of a 30 μm microsieve. Thesuspension is slowly poured onto the stacked microsieves and then washedwith water at least five times. The microspheres collected on the 30 μmmicrosieve is transferred into a ¼ oz glass vial and then dried undervacuum to give 1.43 g of Compound A free base PLGA microspheres with asize distribution of 25-70 μm. The drug content in the obtainedmicrospheres is 8.5%, as determined by HPLC. The initial loading forthis preparation is 16% (calculated based upon 0.4 g of Compound A freebase in 2.1 g of the PLGA polymer). Drug entrapment efficiency is 53%.

Example 8 Preparation of the PLGA (PLA/PLG=75/25, 0.68 dl/g)Microspheres of Compound B Free Base (Lot G)

For purposes of this example, Compound B refers to the compound ofFormula I wherein X is —N(CH₃)— and Y is —CH(OH)—. 2 g of Poly(vinylalcohol) (PVA, 87-89% hydrolyzed, typical molecular weight 13000-23000)in 400 mL of deionized water is sonicated in a bath sonicator for 5-10min and then filtered to give 0.5% PVA aqueous solution. The filtrate istransferred to a 500 mL flat bottom flask. 0.80 g of Compound B (freebase) and 1.2 g of PLGA polymer (PLA/PLG=75/25, 0.32-0.44 dl/g, acid endgroups) are dissolved in 15 mL of dichloromethane. This solution isadded into the 0.5% PVA aqueous solution dropwise with vigorousstirring. A mechanical overhead stirrer is used and the stirring speedis around 700 ppm during the addition. After the completion of theaddition, the mixture is stirred at this speed for an hour and thenstirred at approximately 550 ppm for 4 hours. An argon stream is appliedthroughout the process to promote the evaporation of dichloromethanefrom the aqueous solution. A size 75 μm microsieve is stacked on the topof a 20 μm microsieve. The suspension is slowly poured onto the stackedmicrosieves and then washed with water at least five times. Themicrospheres collected on the 20 μm microsieve is transferred into a 50mL falcon tube with deionized water and then lyophilized to give 1.36 gof Compound B PLGA microspheres with a size distribution of 13-60 μm.The drug content in the obtained microspheres is 29%, as determined byHPLC. The initial loading for this preparation is 40% (calculated basedupon 0.8 g of Compound B free base in 1.2 g of the PLGA polymer). Drugentrapment efficiency is 72.5%.

Example 9 Loading Determination of Long-Acting Injectable Microspheres

About 5 mg of microspheres are dissolved in 10 mL of a 1:2 v/vdichloromethane/acetonitrile mixture. 1 mL of the solution istransferred into 1.5 mL microtube and solvent is removed using theSavant Speed Vac; then the residue is reconstituted in 95%acetonitrile/5% water. This solution is filtered (Waters 0.2 μm Nylonsyringe filter) and measurements are conducted in triplicate via WatersAcquity UPLC with a PDA UV absorbance detector set at 314 nm. The mobilephase is gradient acetonitrile-water with v/v 0.1% formic acid. WatersAcquity UPLC HSS T3 (2.1×50 mm) column is used with the flow rate at 0.3ml/min. A standard curve is prepared to include about 0.1-0.7 mg/mL ofthe expected Compound A concentration.

Drug loading is determined as: percent drugloading=100×(10×concentration of filtered solution)/weight ofmicrospheres used. The results are reported as the mean±SD.

Example 10 Drug Release Determination of Long-Acting InjectableMicrospheres

Microsphere drug release experiments are carried out in 0.1 M phosphatebuffer (pH 7.4) containing 10 mM ascorbic acid. Microsphere suspensionscontaining known amounts of drug (about 30 mg) are placed in aregenerated cellulose membrane dialysis device (Float-a-Lyzer). TheFloat-a-Lyzer is placed in a 45-mL falcon tube containing 40 mL buffer,the release medium maintained at 37° C. and shook horizontally at 100rpm in an oven. The buffer is replaced with fresh solution atpredetermined time intervals. The drug content of the release medium isdetermined via UPLC using UV-vis absorbance at 314 nm with a standardcurve constructed with known concentrations of ITI07 (3˜30 μg/mL).

Example 11 Pharmacokinetics of Long-Acting Injectable Microspheres

For in vivo characterization, in vivo drug release (pharmacokineticstudy) is determined. The pharmacokinetics of the formulation is studiedin adult male Sprague-Dawley rats. Rats (N=12/experiment) are injectedsubcutaneously in the intra-scapular region with a suspension (2 ml/kg)of Compound A free base formulated in biodegradable, PLGA microspheres(about 60 mg/rat) suspended in a solution of 0.5% low viscositycarboxymethylcellulose in sterile saline containing 0.1% Tween-20. Atspecified times after injection (i.e., 24 hours to 28 days) rats (N=2 or3/time point) are tested for 5-HT_(2A) agonist-induced head twitchbehavior as a functional indicator of 5-HT_(2A) antagonist activity dueto circulating Compound A levels. For these measurements rats areinjected intraperitoneally with 2, 5-dimethoxy-4-iodoamphetamine (DOI)(2.5 mg/kg) in a volume of 2 ml/kg. Five minutes later rats are observedfor stereotypic head twitch behaviors which are manually counted andrecorded. Rats are killed by decapitation at specified time points(i.e., 24 h-28 days after injection of the formulation) and trunk bloodand brain tissue is collected for analysis of levels of Compound A andits known metabolites (Compound B), using an HPLC-MS/MS method.

Using a procedure as described or similarly described above, severallong-acting injectable microsphere formulations are analyzed for theirin vivo release profile of the compound of Formula I wherein X is—N(CH₃)— and Y is —C(O)— (Compound A free base). The results aresummarized in the below tables. Table 2 shows the physicalcharacteristics of LAI microsphere formulations 2-7 and 7A. Particlesize distribution is determined using photomicroscopy.

TABLE 2 Actual Initial drug Entrap- Size Inherent drug loading mentdistri- Molecular Viscosity content (wt/wt efficiency bution Ex. Weight(dL/g) (wt/wt %) %) (%) (μm) 2 24K-38K 0.32-0.44 40 38 95 22-57 324K-38K 0.32-0.44 40 38 95 24-48 4 159K 0.89 40 36 90 28-63 5 113K 0.6840 36 90 25-73 6 113K 0.68 40 37 93  75-108 7 113K 0.68 40 37 93  52-1017-A 24K-38K 0.32-0.44 16 8.5 53 25-69Actual drug loading describes the % weight/weight of Compound A in themicrospheres. Microspheres are dosed to the animals at either 60 mg/kgor 30 mg/kg. Compound A dose, in Table 2, represents the amount of drugdosed to the animal (actual drug loading×microsphere dose). Plasma andbrain levels of both Compound A, and the major metabolite of Compound A(Compound B), are measured on Day 1, Day 3, Day 7, Day 10, Day 14 andDay 21 after subcutaneous injection in rats. The results are shown inTable 3.

TABLE 3 Values are Compound A (Compound B) (ng/mL) Ex. Microsphere CompA Day 1 Day 1 Day 3 Day 3 Day 7 Day 7 Day 10 Day 10 Day 14 Day 14 Day 21Day 21 No. dose (mg/kg) dose (mg/kg) plasma brain plasma brain plasmabrain plasma brain plasma brain plasma brain 2 60 22.8 31  300  63 15415  125  8 78 (4) (51) (59) (143) (3) (32) (*) (24) 3 60 22.8 47 170 18 84 0.5 4 (38) (108) (4) (26) (0.4) (3) 5 60 21.6 4 41 72 216 26  127  533 1   4   (0.5) (12) (49) (114) (23)  (65) (1)  (8) (*) (*) 7 30 11.1 113 32 123 8 18 2  9 (1)  (6)  (7)  (28) (2)  (6) (*)  (3) 7-A 60 5.1 354  5  42 10  70 9 69 4   35 1   11    (0.4) (10)   (0.6)  (9)   (1.2)(16) (1) (12) (0.6)  (8) (0.2) (4)It is observed, unexpectedly, that a superior release profile (prolongedrelease) is obtained using a lower microsphere loading. The microsphereformulation having a loading of 8.5% by weight (Ex. 7-A) yields arelease profile with a peak brain level of drug at day 7, withmeasurable levels of drug through day 21 of the study (11 ng/mL brainlevel on day 21). In contrast, the microspheres with higher loading ofdrug result in earlier peak release of drug with no measurable levels orlow levels of drug being maintained beyond day 10 of the study.

The invention claimed is:
 1. A long-acting injectable compositioncomprising polymeric microspheres comprising a PLGA matrix with eithercarboxylic acid or carboxylic ester end groups, and an effective amountof a Compound of Formula I, the Compound of Formula I being dispersed,dissolved or encapsulated in the polymer matrix of the microsphere:

wherein: X is —O—, —NH— or —N(CH₃)—; Y is —O—, —C(R₂)(OH)—, —C(R₃)(OR₁)or —C(O)—; and R₁ is —C₁₋₆alkyl or —C(O)—C₁₋₂₁alkyl, optionallysaturated or unsaturated and optionally substituted with one or morehydroxyl or C₁₋₂₂alkoxy groups, wherein such compound hydrolyzes to formthe residue of a natural or unnatural, saturated or unsaturated fattyacid; R₂ is H or —C₁₋₆alkyl; and R₃ is H or —C₁₋₆alkyl; in free orpharmaceutically acceptable salt form; wherein the composition furthercomprises an antioxidant in an amount effective to inhibit or reduceoxidation of the Compound of Formula I.
 2. The long-acting injectablecomposition according to claim 1, wherein the amount of the Compound ofFormula I is dispersed, dissolved or encapsulated in each microsphere,on average, is from about 5% by weight to about 50% by weight of eachmicrosphere.
 3. The long-acting injectable composition of claim 1,wherein the compound of Formula I is a compound wherein: X is —O—, —NH—or —N(CH₃)—; Y is —O—, —C(H)(OH)—, —C(H)(OR₁) or —C(O)—; and R₁ is—C(O)—C₁₋₂₁alkyl, optionally saturated or unsaturated and optionallysubstituted with one or more hydroxy or C₁₋₂₂alkoxy wherein suchcompound hydrolyzes to form the residue of a natural or unnatural,saturated or unsaturated fatty acid, in free or pharmaceuticallyacceptable salt form.
 4. The long-acting injectable composition of claim1, wherein the compound of Formula I is selected from a group consistingof compounds of formula I wherein: X is —O— and Y is —C(H)(OH)—, X is—NH— and Y is —C(H)(OH)—, X is —N(CH₃)— and Y is —C(H)(OH)—, X is —O—and Y is —C(O)—, X is —O— and Y is —O—, X is —N(CH₃)— and Y is —C(O)—, Xis —N(CH₃)— and Y is —O—, X is —NH— and Y is —C(O)—, X is —NH— and Y is—O—, X is —N(CH₃)— and Y is —C(H)(OR₁), X is —NH— and Y is —C(H)(OR₁),or X is —O— and Y is —C(H)(OR₁); X is —O— and Y is —C(CH₃)(OH)—, X is—NH— and Y is C(CH₃)(OH)—, and X is —N(CH₃)— and Y is C(CH₃)(OH)—, eachin free or pharmaceutically acceptable salt form.
 5. The long-actinginjectable composition of claim 1, wherein the compound of Formula I isa compound wherein X is —N(CH₃)— and Y is —C(O)— or —C(H)(OH), in freepharmaceutically acceptable salt form.
 6. The long-acting injectablecomposition of claim 1, wherein the composition completely degrades andreleases the Compound of Formula I within less than 6 months.
 7. Thelong-acting injectable composition of claim 1, wherein said compositioncompletely degrades and releases the Compound of Formula I within lessthan 4 months.
 8. The long-acting injectable composition of claim 1,wherein the composition completely degrades and releases the Compound ofFormula I within less than 3 months.
 9. The long-acting injectablecomposition of claim 1, wherein the composition completely degrades andreleases the Compound of Formula I within less than 2 months.
 10. Thelong-acting injectable composition of claim 1, wherein the compositioncompletely degrades and releases the Compound of Formula I within lessthan 1 month.
 11. The long-acting injectable composition of claim 1,wherein the composition is formulated for intramuscular,intraperitoneal, intrathecal, epidural or subcutaneous injection. 12.The long-acting injectable composition of claim 11, wherein thecomposition is formulated for intramuscular or subcutaneous injection.13. The long-acting injectable composition of claim 1, whereinantioxidant is selected from butylated hydroxytoluene and butylatedhydroxyanisole.
 14. The long-acting injectable composition according toclaim 1 wherein the effective amount of the compound of Formula I isfrom 100 mg to 600 mg per month.
 15. The long-acting injectablecomposition according to claim 1 wherein the effective amount of thecompound of Formula I is from 150 mg to 300 mg per month.
 16. Thelong-acting injectable composition of claim 1, wherein the Compound ofFormula I is a compound wherein X is —N(CH₃)— and Y is —C(O)—, in freeor pharmaceutically acceptable salt form.
 17. The long-acting injectablecomposition of claim 1, wherein the Compound of Formula I is in freeform.
 18. The long-acting injectable composition of claim 1, wherein theCompound of Formula I is in pharmaceutically acceptable salt form. 19.The long-acting injectable composition of claim 18, wherein thepharmaceutically acceptable sale form is toluene sulfonic acid additionsalt form.
 20. The long-acting injectable composition of claim 1,wherein the Compound of Formula I is a compound wherein X is —N(CH₃)—and Y is —C(O)—, in free form.